Stabilized forms of gp120 polypeptide, nucleic acids encoding these stabilized forms, vectors comprising these nucleic acids, and methods of using these polypeptides, nucleic acids, vectors and host cells are disclosed. Crystal structures and computer systems including atomic coordinates for stabilized forms of gp120, and gp120 with an extended V3 loop, and methods of using these structures and computer systems are also disclosed.
|
9. An isolated nucleic acid molecule comprising the nucleotide sequence encoding the amino acid sequence set forth as SEQ ID NO: 2.
1. An isolated nucleic acid comprising a nucleotide sequence encoding a wild type hiv-1 gp120 polypeptide, or immunogenic fragment thereof, comprising substitutions of cysteines for the amino acids in at least one of residue pairs 96 and 275; 109 and 428; 123 and 431; and 231 and 267, and amino acid substitutions at positions 257 and 375, wherein the polypeptide, or fragment thereof further comprises a tryptophan at position 95 if the polypeptide, or fragment thereof comprises cysteines at residue pairs 96 and 275, and wherein the residue numbers correspond to amino acid positions in the amino acid sequence set forth as SEQ ID NO: 27.
2. The isolated nucleic acid of
7. A method for generating an immune response in a subject, comprising administering to the subject the nucleic acid molecule of
8. The method of
a) monomeric or trimeric gp140 of hiv envelope polypeptide;
b) an unmodified monomeric or trimeric gp120 of hiv envelope polypeptide; or
c) any combination of a-b, above.
14. The method of
a) monomeric or trimeric gp140 of hiv envelope polypeptide;
b) an unmodified monomeric or trimeric gp120 of an hiv envelope polypeptide;
c) a soluble form of CD4; or
d) any combination of a-c, above.
15. The isolated nucleic acid of
16. The isolated nucleic acid of
17. The isolated nucleic acid of
18. The isolated nucleic acid of
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
This is the U.S. §371 National Stage of International Application No. PCT/US2006/034681, filed Sep. 6, 2006, published in English under PCT Article 21(2), which in turn claims the benefit of U.S. Provisional Application No: 60/713,725, filed Sep. 6, 2005; U.S. Provisional Application No: 60/729,878, filed Oct. 24, 2005; U.S. Provisional Application No: 60/731,627, filed Oct. 28, 2005; and U.S. Provisional Application No: 60/832,458, filed Jul. 20, 2006. All of the provisional applications are incorporated by reference herein in their entirety.
The present disclosure relates to stabilized forms of human immunodeficiency virus gp120 envelope protein, specifically to crystalline forms of gp120, high resolution structures obtained from these crystals, and use thereof.
The primary immunologic abnormality resulting from infection by human immunodeficiency virus (HIV) is the progressive depletion and functional impairment of T lymphocytes expressing the CD4 cell surface glycoprotein. The loss of CD4 helper/inducer T cell function probably underlies the profound defects in cellular and humoral immunity leading to the opportunistic infections and malignancies characteristic of the acquired immunodeficiency syndrome (AIDS) (Lane et al., Ann. Rev. Immunol. 3:477, 1985). Studies of HIV-1infection of fractionated CD4 and CD8 T cells from normal donors and AIDS patients have revealed that depletion of CD4 T cells results from the ability of HIV-1 to selectively infect, replicate in, and ultimately destroy this T lymphocyte subset (Klatzmann et al., Science 225:59, 1984). The possibility that CD4 itself is an essential component of the cellular receptor for HIV-1 was first indicated by the observation that monoclonal antibodies directed against CD4 block HIV-1 infection and syncytia induction (Dalgleishet al., Nature 312:767, 1984; McDougal et al., J. Immunol. 135:3151, 1985). This hypothesis has been confirmed by the demonstration that a molecular complex forms between CD4 and the major envelope glycoprotein of HIV-1 (McDougal et al., Science 231:382, 1986).
The major envelope protein of HIV-1 is a glycoprotein of approximately 160 kD (gp160). During infection proteases of the host cell cleave gp160 into gp120 and gp41. gp41 is an integral membrane protein, while gp120 protrudes from the mature virus. Together gp120 and gp41 make up the HIV envelope spike.
The HIV envelope spike mediates binding to receptors and virus entry (Wyatt and Sodroski, Science 280:188, 1998). The spike is trimeric and composed of three gp120 exterior and three gp41 transmembrane envelope glycoproteins. CD4 binding to gp120 in the spike induces conformational changes that allow binding to a coreceptor, either CCR5 or CXCR4, which is required for viral entry (Dalgleish et al., Nature 312:763, 1984; Sattentau and Moore, J. Exp. Med. 174:407, 1991; Feng at al., Science 272:872, 1996; Wu et al., Nature 384:179, 1996; Trkola et al., Nature 384:184, 1996).
The mature gp120 glycoprotein is approximately 470-490 amino acids long depending on the HIV strain of origin. N-linked glycosylation at approximately 20-25 sites makes up nearly half of the mass of the molecule. Sequence analysis shows that the polypeptide is composed of five conserved regions (C1-C5) and five regions of high variability (V1-V5).
With the number of individuals infected by HIV-1 approaching 1% of the world's population, an effective vaccine is urgently needed. An enveloped virus, HIV-1 hides from humoral recognition behind a protective lipid bilayer. An available viral target for neutralizing antibodies is the envelope spike. Genetic, immunologic and structural studies of the HIV-1 envelope glycoproteins have revealed extraordinary diversity as well as multiple overlapping mechanisms of humoral evasion, including self-masquerading glycan, immunodominant variable loops, and conformational masking. These evolutionarily honed barriers of diversity and evasion have confounded traditional means of vaccine development. It is believed that immunization with effectively immunogenic HIV gp120 envelope glycoprotein can elicit a neutralizing response directed against gp120, and thus HIV. The need exists for immunogens that are capable of eliciting an immunogenic response in a suitable subject. In order to be effective, the antibodies raised must be capable of neutralizing a broad range of HIV strains and subtypes.
Disclosed herein are gp120 polypeptides and nucleic acid molecules encoding gp120 polypeptides, which are useful to induce an immunogenic response to a lentivirus, such as SIV or HIV (for example HIV-1 and HIV-2) in a subject. In several embodiments, the gp120 polypeptides are stabilized in a CD4 bound conformation by the introduction of a plurality of non-naturally occurring cross-linking cysteine residues. In other examples, the gp120 polypeptide has the V3 loop in an extended conformation.
Immunogenic compositions containing a therapeutically effective amount of gp120 polypeptides and nucleic acid molecules encoding gp120 polypeptides are also disclosed. Also disclosed are methods for eliciting and/or enhancing an immune response in a subject, for example by administering an immunogenic composition.
Crystalline forms of gp120 are disclosed as are crystal structures of gp120 polypeptides obtained from these structures. Methods are also disclosed for identifying an immunogen that induces an immune response to gp120 using these crystal structures. Also provided by this disclosure is a machine readable data storage medium including a data storage material encoded with machine readable data corresponding to the coordinates of the crystal structures disclosed herein. A computer system is disclosed for displaying the coordinate data from these crystal structures of gp120, such as the atomic positions, surface, domain, or region of the gp120 polypeptide.
The foregoing and other objects, features, and advantages of the invention will become more apparent from the following detailed description, which proceeds with reference to the accompanying figures.
The nucleic and amino acid sequences listed in the accompanying sequence listing are shown using standard letter abbreviations for nucleotide bases, and three letter code for amino acids, as defined in 37 C.F.R. 1.822. Only one strand of each nucleic acid sequence is shown, but the complementary strand is understood as included by any reference to the displayed strand.
Mutant location
M95W
T257S
W96C
I109C
T123C
K231C
K231C
Mutant Name
New name
S375W
A433M
V275C
Q428C
G431C
E267C
E268C
WT core
WT core
C2
C3
C1S1
S2
S3
S4
S5
2a
C2
x
4-0
C2S5
x
x
4a
C2S2
x
x
4b
C2S4
x
x
4c
C2S3
x
x
5mut
C12S1
x
x
6a
C123S1
x
x
x
6b
C2S24
x
x
x
8a
C123S14
x
x
x
x
8b
C123S12
x
x
x
x
9a
C23S234
x
x
x
x
x
8c
C2S234
x
x
x
x
10a
C123S124
x
x
x
x
x
9b
C12S134
x
x
x
x
10c
C123S134
x
x
x
x
x
9c
C12S123
x
x
x
x
10b
C123S123
x
x
x
x
x
11a
C12S1234
x
x
x
x
x
I. Terms
Unless otherwise noted, technical terms are used according to conventional usage. Definitions of common terms in molecular biology can be found in Benjamin Lewin, Genes V, published by Oxford University Press, 1994 (ISBN 0-19-854287-9); Kendrew et al. (eds.), The Encyclopedia of Molecular Biology, published by Blackwell Science Ltd., 1994 (ISBN 0-632-02182-9); and Robert A. Meyers (ed.), Molecular Biology and Biotechnology: a Comprehensive Desk Reference, published by VCH Publishers, Inc., 1995 (ISBN 1-56081-569-8). Terms describing protein structure and structural elements of proteins can be found in Creighton, Proteins, Structures and Molecular Properties, W.H. Freeman & Co., New York, 1993 (ISBN 0-717-7030) which is incorporated by reference herein in its entirety.
Unless otherwise explained, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. The singular terms “a,” “an,” and “the” include plural referents unless context clearly indicates otherwise. Similarly, the word “or” is intended to include “and” unless the context clearly indicates otherwise. It is further to be understood that all base sizes or amino acid sizes, and all molecular weight or molecular mass values, given for nucleic acids or polypeptides are approximate, and are provided for description. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of this disclosure, suitable methods and materials are described below. The term “comprises” means “includes.” The abbreviation, “e.g.” is derived from the Latin exempli gratia, and is used herein to indicate a non-limiting example. Thus, the abbreviation “e.g.” is synonymous with the term “for example.”
All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including explanations of terms, will control. In addition, all the materials, methods, and examples are illustrative and not intended to be limiting. In order to facilitate review of the various embodiments of the disclosure, the following explanations of specific terms are provided:
Adjuvant: A vehicle used to enhance antigenicity; such as a suspension of minerals (alum, aluminum hydroxide, aluminum phosphate) on which antigen is adsorbed; or water-in-oil emulsion in which antigen solution is emulsified in oil (MF-59, Freund's incomplete adjuvant), sometimes with the inclusion of killed mycobacteria (Freund's complete adjuvant) to further enhance antigenicity (inhibits degradation of antigen and/or causes influx of macrophages). Adjuvants also include immunostimulatory molecules, such as cytokines, costimulatory molecules, and for example, immunostimulatory DNA or RNA molecules, such as CpG oligonucleotides.
Administration: The introduction of a composition into a subject by a chosen route. For example, if the chosen route is intravenous, the composition is administered by introducing the composition into a vein of the subject.
Antibody: A polypeptide substantially encoded by an immunoglobulin gene or immunoglobulin genes, or fragments thereof, which specifically binds and recognizes an analyte (antigen) such as gp120 or an antigenic fragment of gp120. Immunoglobulin genes include the kappa, lambda, alpha, gamma, delta, epsilon and mu constant region genes, as well as the myriad immunoglobulin variable region genes.
Antibodies exist, for example as intact immunoglobulins and as a number of well characterized fragments produced by digestion with various peptidases. For instance, Fabs, Fvs, and single-chain Fvs (SCFvs) that bind to gp120 or fragments of gp120 would be gp120-specific binding agents. This includes intact immunoglobulins and the variants and portions of them well known in the art, such as Fab′ fragments, F(ab)′2 fragments, single chain Fv proteins (“scFv”), and disulfide stabilized Fv proteins (“dsFv”). A scFv protein is a fusion protein in which a light chain variable region of an immunoglobulin and a heavy chain variable region of an immunoglobulin are bound by a linker, while in dsFvs, the chains have been mutated to introduce a disulfide bond to stabilize the association of the chains. The term also includes genetically engineered forms such as chimeric antibodies (such as humanized murine antibodies), heteroconjugate antibodies such as bispecific antibodies). See also, Pierce Catalog and Handbook, 1994-1995 (Pierce Chemical Co., Rockford, Ill.); Kuby, J., Immunology, 3rd Ed., W.H. Freeman & Co., New York, 1997.
Antibody fragments are defined as follows: (1) Fab, the fragment which contains a monovalent antigen-binding fragment of an antibody molecule produced by digestion of whole antibody with the enzyme papain to yield an intact light chain and a portion of one heavy chain; (2) Fab′, the fragment of an antibody molecule obtained by treating whole antibody with pepsin, followed by reduction, to yield an intact light chain and a portion of the heavy chain; two Fab′ fragments are obtained per antibody molecule; (3) (Fab′)2, the fragment of the antibody obtained by treating whole antibody with the enzyme pepsin without subsequent reduction; (4) F(ab′)2, a dimer of two Fab′ fragments held together by two disulfide bonds; (5) Fv, a genetically engineered fragment containing the variable region of the light chain and the variable region of the heavy chain expressed as two chains; and (6) single chain antibody (“SCA”), a genetically engineered molecule containing the variable region of the light chain, the variable region of the heavy chain, linked by a suitable polypeptide linker as a genetically fused single chain molecule. The term “antibody,” as used herein, also includes antibody fragments either produced by the modification of whole antibodies or those synthesized de novo using recombinant DNA methodologies.
Typically, a naturally occurring immunoglobulin has heavy (H) chains and light (L) chains interconnected by disulfide bonds. There are two types of light chain, lambda (λ) and kappa (κ). There are five main heavy chain classes (or isotypes) which determine the functional activity of an antibody molecule: IgM, IgD, IgG, IgA and IgE.
Each heavy and light chain contains a constant region and a variable region, (the regions are also known as “domains”). In combination, the heavy and the light chain variable regions specifically bind the antigen. Light and heavy chain variable regions contain a “framework” region interrupted by three hypervariable regions, also called “complementarity-determining regions” or “CDRs.” The extent of the framework region and CDRs have been defined (see, Kabat et al., Sequences of Proteins of Immunological Interest, U.S. Department of Health and Human Services, 1991, which is hereby incorporated by reference). The Kabat database is now maintained online. The sequences of the framework regions of different light or heavy chains are relatively conserved within a species. The framework region of an antibody, that is the combined framework regions of the constituent light and heavy chains, serves to position and align the CDRs in three-dimensional space.
The CDRs are primarily responsible for binding to an epitope of an antigen. The CDRs of each chain are typically referred to as CDR1, CDR2, and CDR3, numbered sequentially starting from the N-terminus, and are also typically identified by the chain in which the particular CDR is located. Thus, a VH CDR3 is located in the variable domain of the heavy chain of the antibody in which it is found, whereas a VL CDR1 is the CDR1 from the variable domain of the light chain of the antibody in which it is found. Light chain CDRs are sometimes referred to as CDR L1, CDR L2, and CDR L3. Heavy chain CDRs are sometimes referred to as CDR H1, CDR H2, and CDR H3.
References to “VH” or “VH” refer to the variable region of an immunoglobulin heavy chain, including that of an Fv, scFv, dsFv or Fab. References to “VL” or “VL” refer to the variable region of an immunoglobulin light chain, including that of an Fv, scFv, dsFv or Fab.
A “monoclonal antibody” is an antibody produced by a single clone of B-lymphocytes or by a cell into which the light and heavy chain genes of a single antibody have been transfected. Monoclonal antibodies are produced by methods known to those of skill in the art, for instance by making hybrid antibody-forming cells from a fusion of myeloma cells with immune spleen cells. These fused cells and their progeny are termed “hybridomas.” Monoclonal antibodies include humanized monoclonal antibodies.
A “humanized” immunoglobulin is an immunoglobulin including a human framework region and one or more CDRs from a non-human (such as a mouse, rat, or synthetic) immunoglobulin. The non-human immunoglobulin providing the CDRs is termed a “donor,” and the human immunoglobulin providing the framework is termed an “acceptor.” In one embodiment, all the CDRs are from the donor immunoglobulin in a humanized immunoglobulin. Constant regions need not be present, but if they are, they must be substantially identical to human immunoglobulin constant regions, such as at least about 85-90%, such as about 95% or more identical. Hence, all parts of a humanized immunoglobulin, except possibly the CDRs, are substantially identical to corresponding parts of natural human immunoglobulin sequences. A “humanized antibody” is an antibody comprising a humanized light chain and a humanized heavy chain immunoglobulin. A humanized antibody binds to the same antigen as the donor antibody that provides the CDRs. The acceptor framework of a humanized immunoglobulin or antibody may have a limited number of substitutions by amino acids taken from the donor framework. Humanized or other monoclonal antibodies can have additional conservative amino acid substitutions which have substantially no effect on antigen binding or other immunoglobulin functions. Humanized immunoglobulins can be constructed by means of genetic engineering (for example, see U.S. Pat. No. 5,585,089).
Antigenic gp120 polypeptide: An “antigenic gp120 polypeptide” includes a gp120 molecule or a portion thereof that is capable of provoking an immune response in a mammal, such as a mammal with or without an HIV infection. Administration of an antigenic gp120 polypeptide that provokes an immune response preferably leads to protective immunity against HIV.
Antigenic surface: A surface of a molecule, for example a protein such as a gp120 protein or polypeptide, capable of eliciting an immune response. An antigenic surface includes the defining features of that surface, for example the three-dimensional shape and the surface charge. An antigenic surface includes both surfaces that occur on gp120 polypeptides as well as surfaces of compounds that mimic the surface of a gp120 polypeptide (mimetics).
CD4: Cluster of differentiation factor 4 polypeptide, a T-cell surface protein that mediates interaction with the MHC class II molecule. CD4 also serves as the primary receptor site for HIV on T-cells during HIV-1 infection.
The known sequence of the CD4 precursor has a hydrophobic signal peptide, an extracellular region of approximately 370 amino acids, a highly hydrophobic stretch with significant identity to the membrane-spanning domain of the class II MHC beta chain, and a highly charged intracellular sequence of 40 resides (Maddon, Cell 42:93, 1985).
The term “CD4” includes polypeptide molecules that are derived from CD4 include fragments of CD4, generated either by chemical (for example enzymatic) digestion or genetic engineering means. Such a fragment may be one or more entire CD4 protein domains. The extracellular domain of CD4 consists of four contiguous immunoglobulin-like regions (D1, D2, D3, and D4, see Sakihama et al., Proc. Natl. Acad. Sci. 92:6444, 1995; U.S. Pat. No. 6,117,655), and amino acids 1 to 183 have been shown to be involved in gp120 binding. For instance, a binding molecule or binding domain derived from CD4 would comprise a sufficient portion of the CD4 protein to mediate specific and functional interaction between the binding fragment and a native or viral binding site of CD4. One such binding fragment includes both the D1 and D2 extracellular domains of CD4 (D1D2 is also a fragment of soluble CD4 or sCD4 which is comprised of D1D2 D3 and D4), although smaller fragments may also provide specific and functional CD4-like binding. The gp120-binding site has been mapped to D1 of CD4.
CD4 polypeptides also include “CD4-derived molecules” which encompasses analogs (non-protein organic molecules), derivatives (chemically functionalized protein molecules obtained starting with the disclosed protein sequences) or mimetics (three-dimensionally similar chemicals) of the native CD4 structure, as well as proteins sequence variants or genetic alleles that maintain the ability to functionally bind to a target molecule.
CD4BS antibodies: Antibodies that bind to or substantially overlap the CD4 binding surface of a gp120 polypeptide. The antibodies interfere with or prevent CD4 from binding to a gp120 polypeptide.
CD4i antibodies: Antibodies that bind to a conformation of gp120 induced by CD4 binding.
Contacting: Placement in direct physical association; includes both in solid and liquid form.
Computer readable media: Any medium or media, which can be read and accessed directly by a computer, so that the media is suitable for use in a computer system. Such media include, but are not limited to: magnetic storage media such as floppy discs, hard disc storage medium and magnetic tape; optical storage media such as optical discs or CD-ROM; electrical storage media such as RAM and ROM; and hybrids of these categories such as magnetic/optical storage media.
Computer system: Hardware that can be used to analyze atomic coordinate data. The minimum hardware of a computer-based system typically comprises a central processing unit (CPU), an input device, for example a mouse, keyboard, and the like, an output device, and a data storage device. Desirably a monitor is provided to visualize structure data. The data storage device may be RAM or other means for accessing computer readable. Examples of such systems are microcomputer workstations available from Silicon Graphics Incorporated and Sun Microsystems running Unix based Windows NT or IBM OS/2 operating systems.
Degenerate variant and conservative variant: A polynucleotide encoding a polypeptide or an antibody that includes a sequence that is degenerate as a result of the genetic code. For example, a polynucleotide encoding a gp120 polypeptide or an antibody that binds gp120 that includes a sequence that is degenerate as a result of the genetic code. There are 20 natural amino acids, most of which are specified by more than one codon. Therefore, all degenerate nucleotide sequences are included as long as the amino acid sequence of the gp120 polypeptide or antibody that binds gp120 encoded by the nucleotide sequence is unchanged. Because of the degeneracy of the genetic code, a large number of functionally identical nucleic acids encode any given polypeptide. For instance, the codons CGU, CGC, CGA, CGG, AGA, and AGG all encode the amino acid arginine. Thus, at every position where an arginine is specified within a protein encoding sequence, the codon can be altered to any of the corresponding codons described without altering the encoded protein. Such nucleic acid variations are “silent variations,” which are one species of conservative variations. Each nucleic acid sequence herein that encodes a polypeptide also describes every possible silent variation. One of skill will recognize that each codon in a nucleic acid (except AUG, which is ordinarily the only codon for methionine) can be modified to yield a functionally identical molecule by standard techniques. Accordingly, each “silent variation” of a nucleic acid which encodes a polypeptide is implicit in each described sequence.
Furthermore, one of ordinary skill will recognize that individual substitutions, deletions or additions which alter, add or delete a single amino acid or a small percentage of amino acids (for instance less than 5%, in some embodiments less than 1%) in an encoded sequence are conservative variations where the alterations result in the substitution of an amino acid with a chemically similar amino acid.
Conservative amino acid substitutions providing functionally similar amino acids are well known in the art. The following six groups each contain amino acids that are conservative substitutions for one another:
1) Alanine (A), Serine (S), Threonine (T);
2) Aspartic acid (D), Glutamic acid (E);
3) Asparagine (N), Glutamine (Q);
4) Arginine (R), Lysine (K);
5) Isoleucine (I), Leucine (L), Methionine (M), Valine (V); and
6) Phenylalanine (F), Tyrosine (Y), Tryptophan (W).
Not all residue positions within a protein will tolerate an otherwise “conservative” substitution. For instance, if an amino acid residue is essential for a function of the protein, even an otherwise conservative substitution may disrupt that activity.
Epitope: An antigenic determinant. These are particular chemical groups or peptide sequences on a molecule that are antigenic, such that they elicit a specific immune response. An antibody binds a particular antigenic epitope, such as an epitope of a gp120 polypeptide.
Expression: Translation of a nucleic acid into a protein. Proteins may be expressed and remain intracellular, become a component of the cell surface membrane, or be secreted into the extracellular matrix or medium.
Expression Control Sequences: Nucleic acid sequences that regulate the expression of a heterologous nucleic acid sequence to which it is operatively linked. Expression control sequences are operatively linked to a nucleic acid sequence when the expression control sequences control and regulate the transcription and, as appropriate, translation of the nucleic acid sequence. Thus expression control sequences can include appropriate promoters, enhancers, transcription terminators, a start codon (ATG) in front of a protein-encoding gene, splicing signal for introns, maintenance of the correct reading frame of that gene to permit proper translation of mRNA, and stop codons. The term “control sequences” is intended to include, at a minimum, components whose presence can influence expression, and can also include additional components whose presence is advantageous, for example, leader sequences and fusion partner sequences. Expression control sequences can include a promoter.
A promoter is a minimal sequence sufficient to direct transcription. Also included are those promoter elements which are sufficient to render promoter-dependent gene expression controllable for cell-type specific, tissue-specific, or inducible by external signals or agents; such elements may be located in the 5′ or 3′ regions of the gene. Both constitutive and inducible promoters are included (see for example, Bitter et al., Methods in Enzymology 153:516-544, 1987). For example, when cloning in bacterial systems, inducible promoters such as pL of bacteriophage lambda, plac, ptrp, ptac (ptrp-lac hybrid promoter) and the like may be used. In one embodiment, when cloning in mammalian cell systems, promoters derived from the genome of mammalian cells (such as metallothionein promoter) or from mammalian viruses (such as the retrovirus long terminal repeat; the adenovirus late promoter; the vaccinia virus 7.5K promoter) can be used. Promoters produced by recombinant DNA or synthetic techniques may also be used to provide for transcription of the nucleic acid sequences.
A polynucleotide can be inserted into an expression vector that contains a promoter sequence which facilitates the efficient transcription of the inserted genetic sequence of the host. The expression vector typically contains an origin of replication, a promoter, as well as specific nucleic acid sequences that allow phenotypic selection of the transformed cells.
gp120: The envelope protein from Human Immunodeficiency Virus (HIV). The envelope protein is initially synthesized as a longer precursor protein of 845-870 amino acids in size, designated gp160. Gp160 forms a homotrimer and undergoes glycosylation within the Golgi apparatus. It is then cleaved by a cellular protease into gp120 and gp41. Gp41 contains a transmembrane domain and remains in a trimeric configuration; it interacts with gp120 in a non-covalent manner. Gp120 contains most of the external, surface-exposed, domains of the envelope glycoprotein complex, and it is gp120 which binds both to the cellular CD4 receptor and to the cellular chemokine receptors (such as CCR5).
The mature gp120 wildtype polypeptides have about 500 amino acids in the primary sequence. Gp120 is heavily N-glycosylated giving rise to an apparent molecular weight of 120 kD. The polypeptide is comprised of five conserved regions (C1-C5) and five regions of high variability (V1-V5). Exemplary sequence of wt gp160 polypeptides are shown on GENBANK, for example accession numbers AAB05604 and AAD12142
The gp120 core has a unique molecular structure, which comprises two domains: an “inner” domain (which faces gp41) and an “outer” domain (which is mostly exposed on the surface of the oligomeric envelope glycoprotein complex). The two gp120 domains are separated by a “bridging sheet” that is not part of either domain. The gp120 core comprises 25 beta strands, 5 alpha helices, and 10 defined loop segments.
“Stabilized gp120” is a form of gp120 polypeptide from HIV-1, characterized by an increase in Tm over the wild type gp120. In some examples the gp120 is stabilized by the replacement of at least two amino acids of gp120 with cysteines such that a disulfide bond can form, wherein the gp120 protein has a Tm of greater than about 53.8° C. The stabilized gp120 mutants may contain amino acid substitutions that fill cavities present in the core of native gp120. The stabilized gp120 can bind CD4. Stabilized forms of gp120 may include forms that have synthetic amino acids. Several exemplary stabilized gp120 proteins are disclosed herein.
Gp120 polypeptides also include “gp120-derived molecules” which encompasses analogs (non-protein organic molecules), derivatives (chemically functionalized protein molecules obtained starting with the disclosed protein sequences) or mimetics (three-dimensionally similar chemicals) of the native gp120 structure, as well as proteins sequence variants (such as mutants), genetic alleles, fusions proteins of gp120, or combinations thereof.
The third variable region referred to herein as the V3 loop is a loop of about 35 amino acids critical for the binding of the co-receptor and determination of which of the co-receptors will bind. In certain examples the V3 loop comprises residues 296-331.
The numbering used in gp120 polypeptides disclosed herein is relative to the HXB2 numbering scheme as set forth in Numbering Positions in HIV Relative to HXB2CG Bette Korber et al., Human Retroviruses and AIDS 1998: A Compilation and Analysis of Nucleic Acid and Amino Acid Sequences. Korber B, Kuiken C L, Foley B, Hahn B, McCutchan F, Mellors J W, and Sodroski J, Eds. Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, N. Mex. which is incorporated by reference herein in its entirety. For reference, the amino acid sequence of HXB2CG is given below as SEQ ID NO: 27: lwvtvyygvpvwkeatttlfcasdakaydtevhnvwathacvptdpnpqevvlvnvtenfnmwkndmveqmhediislwdqslkpcvkltplcvslkctdlkndtntnsssgrmimekgeiknicsfnistsirgkvqkeyaffykldiipidndttsykltscntsvitqacpkvsfepipihycapagfailkcnnktfngtgpctnvstvqcthgirpvvstqlllngslaeeevvirsvnftdnaktiivqlntsveinctrpnnntrkririqrgpgrafvtigkignmrqahcnisrakwnntlkqiasklreqfgnnktiifkqssggdpeivthsfncggeffycnstqlfnstwfnstwstegsnntegsdtitlpcrikqiinmwqkvgkamyappisgqircssnitgllltrdggnsnneseifrpgggdmrdnwrselykykyvvkieplgvaptkakarrvvqrekr (SEQ ID NO: 27). HXB2 is also known as: HXBc2, for HXB clone 2; HXB2R, in the Los Alamos HIV database, with the R for revised, as it was slightly revised relative to the original HXB2 sequence; and HXB2CG in GenBank, for HXB2 complete genome.
Heavy atom derivatization: A method of producing a chemically modified form of a protein crystal, for example a crystal containing gp120. In practice, a crystal is soaked in a solution containing heavy metal atom salts, or organometallic compounds, such as lead chloride, gold thiomalate, thimerosal or uranyl acetate, which can diffuse through the solvent channels of the crystal and bind the surface of the protein. The location(s) of the bound heavy metal atom(s) can be determined by X-ray diffraction analysis of the soaked crystal. This information, in turn, is used to generate the phase information used to construct three-dimensional structure of the enzyme (see Blundel and Johnson, Protein Crystallography, Academic Press (1976).
Host cells: Cells in which a vector can be propagated and its DNA expressed. The cell may be prokaryotic or eukaryotic. The term also includes any progeny of the subject host cell. It is understood that all progeny may not be identical to the parental cell since there may be mutations that occur during replication. However, such progeny are included when the term “host cell” is used.
In silico: A process performed virtually within a computer. For example, using a computer, a virtual compound can be screened for surface similarity or conversely surface complementarity to a virtual representation of the atomic positions at least a portion of a gp120 polypeptide, for example as stabilized gp120, such as defined in Table 1 or a gp120 with an extended V3 loop, such as defined in Table 2.
Immune response: A response of a cell of the immune system, such as a B cell, T cell, or monocyte, to a stimulus. In one embodiment, the response is specific for a particular antigen (an “antigen-specific response”). In one embodiment, an immune response is a T cell response, such as a CD4+ response or a CD8+ response. In another embodiment, the response is a B cell response, and results in the production of specific antibodies.
Immunogenic peptide: A peptide which comprises an allele-specific motif or other sequence, such as an N-terminal repeat, such that the peptide will bind an MHC molecule and induce a cytotoxic T lymphocyte (“CTL”) response, or a B cell response (for example antibody production) against the antigen from which the immunogenic peptide is derived.
In one embodiment, immunogenic peptides are identified using sequence motifs or other methods, such as neural net or polynomial determinations known in the art. Typically, algorithms are used to determine the “binding threshold” of peptides to select those with scores that give them a high probability of binding at a certain affinity and will be immunogenic. The algorithms are based either on the effects on MHC binding of a particular amino acid at a particular position, the effects on antibody binding of a particular amino acid at a particular position, or the effects on binding of a particular substitution in a motif-containing peptide. Within the context of an immunogenic peptide, a “conserved residue” is one which appears in a significantly higher frequency than would be expected by random distribution at a particular position in a peptide. In one embodiment, a conserved residue is one where the MHC structure may provide a contact point with the immunogenic peptide. In one specific non-limiting example, an immunogenic polypeptide includes a region of gp120, or a fragment thereof.
Immunogenic composition: A composition comprising an immunogenic peptide that induces a measurable CTL response against virus expressing the immunogenic peptide, or induces a measurable B cell response (such as production of antibodies) against the immunogenic peptide. In one example an “immunogenic composition” is composition comprising a gp120 polypeptide that induces a measurable CTL response against virus expressing gp120 polypeptide, or induces a measurable B cell response (such as production of antibodies) against a gp120 polypeptide. It further refers to isolated nucleic acids encoding an immunogenic peptide, such as a nucleic acid that can be used to express the gp120 polypeptide (and thus be used to elicit an immune response against this polypeptide).
For in vitro use, an immunogenic composition may consist of the isolated protein, peptide epitope, or nucleic acid encoding the protein, or peptide epitope. For in vivo use, the immunogenic composition will typically comprise the protein or immunogenic peptide in pharmaceutically acceptable carriers, and/or other agents. Any particular peptide, such as a gp120 polypeptide, or nucleic acid encoding the polypeptide, can be readily tested for its ability to induce a CTL or B cell response by art-recognized assays. Immunogenic compositions can include adjuvants, which are well known to one of skill in the art.
Immunologically reactive conditions: Includes reference to conditions which allow an antibody raised against a particular epitope to bind to that epitope to a detectably greater degree than, and/or to the substantial exclusion of, binding to substantially all other epitopes. Immunologically reactive conditions are dependent upon the format of the antibody binding reaction and typically are those utilized in immunoassay protocols or those conditions encountered in vivo. The immunologically reactive conditions employed in the methods are “physiological conditions” which include reference to conditions (such as temperature, osmolarity, pH) that are typical inside a living mammal or a mammalian cell. While it is recognized that some organs are subject to extreme conditions, the intra-organismal and intracellular environment is normally about pH 7 (such as from pH 6.0 to pH 8.0, more typically pH 6.5 to 7.5), contains water as the predominant solvent, and exists at a temperature above 0° C. and below 50° C. Osmolarity is within the range that is supportive of cell viability and proliferation.
Immunotherapy: A method of evoking an immune response against a virus based on their production of target antigens. Immunotherapy based on cell-mediated immune responses involves generating a cell-mediated response to cells that produce particular antigenic determinants, while immunotherapy based on humoral immune responses involves generating specific antibodies to virus that produce particular antigenic determinants.
Inhibiting or treating a disease: Inhibiting the full development of a disease or condition, for example, in a subject who is at risk for a disease such as acquired immune deficiency syndrome (AIDS), AIDS related conditions, HIV-1 infection, or combinations thereof. “Treatment” refers to a therapeutic intervention that ameliorates a sign or symptom of a disease or pathological condition after it has begun to develop. The term “ameliorating,” with reference to a disease or pathological condition, refers to any observable beneficial effect of the treatment. The beneficial effect can be evidenced, for example, by a delayed onset of clinical symptoms of the disease in a susceptible subject, a reduction in severity of some or all clinical symptoms of the disease, a slower progression of the disease, a reduction in the number of metastases, an improvement in the overall health or well-being of the subject, or by other parameters well known in the art that are specific to the particular disease. A “prophylactic” treatment is a treatment administered to a subject who does not exhibit signs of a disease or exhibits only early signs for the purpose of decreasing the risk of developing pathology.
Isolated: An “isolated” biological component (such as a nucleic acid, peptide or protein) has been substantially separated, produced apart from, or purified away from other biological components in the cell of the organism in which the component naturally occurs, such as, other chromosomal and extrachromosomal DNA and RNA, and proteins. Nucleic acids, peptides and proteins which have been “isolated” thus include nucleic acids and proteins purified by standard purification methods. The term also embraces nucleic acids, peptides, and proteins prepared by recombinant expression in a host cell as well as chemically synthesized nucleic acids.
Kd: The dissociation constant for a given interaction, such as a polypeptide ligand interaction. For example, for the bimolecular interaction of CD4 and gp120 it is the concentration of the individual components of the bimolecular interaction divided by the concentration of the complex.
Leukocyte: Cells in the blood, also termed “white cells,” that are involved in defending the body against infective organisms and foreign substances. Leukocytes are produced in the bone marrow. There are 5 main types of white blood cell, subdivided between 2 main groups: polymorphonuclear leukocytes (neutrophils, eosinophils, basophils) and mononuclear leukocytes (monocytes and lymphocytes).
Ligand: Any molecule which specifically binds a protein, such as a gp120 protein, and includes, inter alia, antibodies that specifically bind a gp120 protein. In alternative embodiments, the ligand is a protein or a small molecule (one with a molecular weight less than 6 kiloDaltons).
Mimetic: A molecule (such as an organic chemical compound) that mimics the activity of an agent, such as the activity of a gp120 protein, for example by inducing an immune response to gp120. Peptidomimetic and organomimetic embodiments are within the scope of this term, whereby the three-dimensional arrangement of the chemical constituents of such peptido- and organomimetics mimic the three-dimensional arrangement of the peptide backbone and component amino acid side chains in the peptide, resulting in such peptido- and organomimetics of the peptides having substantial specific activity. For computer modeling applications, a pharmacophore is an idealized, three-dimensional definition of the structural requirements for biological activity. Peptido- and organomimetics can be designed to fit each pharmacophore with computer modeling software (using computer assisted drug design or CADD). See Walters, “Computer-Assisted Modeling of Drugs”, in Klegerman & Groves, eds., 1993, Pharmaceutical Biotechnology, Interpharm Press: Buffalo Grove, Ill., pp. 165-174 and Principles of Pharmacology (ed. Munson, 1995), chapter 102 for a description of techniques used in computer assisted drug design.
Molecular Replacement: A method that involves generating a preliminary model, such as a model of a gp120 polypeptide, whose structure coordinates are unknown, by orienting and positioning a molecule whose structure coordinates are known (such as coordinates from Table 1) within the unit cell of the unknown crystal so as best to account for the observed diffraction pattern of the unknown crystal. Phases can then be calculated from this model and combined with the observed amplitudes to give an approximate Fourier synthesis of the structure whose coordinates are unknown. This, in turn, can be subject to any of the several forms of refinement to provide a final, accurate structure of the unknown molecule (see Lattman, Methods in Enzymology, 115:55-77, 1985; Rossmann, ed., “The Molecular Replacement Method”, Int. Sci. Rev. Ser., No. 13, Gordon & Breach, New York, 1972). Using the structure coordinates of gp120, such as a stabilized gp120 provided herein; molecular replacement may be used to determine the structure coordinates of a crystalline mutant or homologue of gp120, a different crystal form of gp120, or gp120 in complex with another molecule, such as an antibody, cell surface receptor, or combination thereof.
Naturally Occurring Amino Acids: L-isomers of the naturally occurring amino acids. The naturally occurring amino acids are glycine, alanine, valine, leucine, isoleucine, serine, methionine, threonine, phenylalanine, tyrosine, tryptophan, cysteine, proline, histidine, aspartic acid, asparagine, glutamic acid, glutamine, gamma.-carboxyglutamic acid, arginine, ornithine and lysine. Unless specifically indicated, all amino acids referred to in this application are in the L-form. “Synthetic amino acids” refers to amino acids that are not naturally found in proteins. Examples of synthetic amino acids used herein, include racemic mixtures of selenocysteine and selenomethionine. In addition, unnatural amino acids include the D or L forms of nor-leucine, para-nitrophenylalanine, homophenylalanine, para-fluorophenylalanine, 3-amino-2-benzylpropionic acid, homoarginine, and D-phenylalanine. The term “positively charged amino acid” refers to any naturally occurring or synthetic amino acid having a positively charged side chain under normal physiological conditions. Examples of positively charged naturally occurring amino acids are arginine, lysine and histidine. The term “negatively charged amino acid” refers to any naturally occurring or synthetic amino acid having a negatively charged side chain under normal physiological conditions. Examples of negatively charged naturally occurring amino acids are aspartic acid and glutamic acid. The term “hydrophobic amino acid” refers to any amino acid having an uncharged, nonpolar side chain that is relatively insoluble in water. Examples of naturally occurring hydrophobic amino acids are alanine, leucine, isoleucine, valine, proline, phenylalanine, tryptophan and methionine. The term “hydrophilic amino acid” refers to any amino acid having an uncharged, polar side chain that is relatively soluble in water. Examples of naturally occurring hydrophilic amino acids are serine, threonine, tyrosine, asparagine, glutamine, and cysteine.
Nucleic acid: A polymer composed of nucleotide units (ribonucleotides, deoxyribonucleotides, related naturally occurring structural variants, and synthetic non-naturally occurring analogs thereof) linked via phosphodiester bonds, related naturally occurring structural variants, and synthetic non-naturally occurring analogs thereof. Thus, the term includes nucleotide polymers in which the nucleotides and the linkages between them include non-naturally occurring synthetic analogs, such as, for example and without limitation, phosphorothioates, phosphoramidates, methyl phosphonates, chiral-methyl phosphonates, 2-O-methyl ribonucleotides, peptide-nucleic acids (PNAs), and the like. Such polynucleotides can be synthesized, for example, using an automated DNA synthesizer. The term “oligonucleotide” typically refers to short polynucleotides, generally no greater than about 50 nucleotides. It will be understood that when a nucleotide sequence is represented by a DNA sequence (i.e., A, T, G, C), this also includes an RNA sequence (i.e., A, U, G, C) in which “U” replaces “T.”
“Nucleotide” includes, but is not limited to, a monomer that includes a base linked to a sugar, such as a pyrimidine, purine or synthetic analogs thereof, or a base linked to an amino acid, as in a peptide nucleic acid (PNA). A nucleotide is one monomer in a polynucleotide. A nucleotide sequence refers to the sequence of bases in a polynucleotide. A gp120 polynucleotide is a nucleic acid encoding a gp120 polypeptide.
Conventional notation is used herein to describe nucleotide sequences: the left-hand end of a single-stranded nucleotide sequence is the 5′-end; the left-hand direction of a double-stranded nucleotide sequence is referred to as the 5′-direction. The direction of 5′ to 3′ addition of nucleotides to nascent RNA transcripts is referred to as the transcription direction. The DNA strand having the same sequence as an mRNA is referred to as the “coding strand;” sequences on the DNA strand having the same sequence as an mRNA transcribed from that DNA and which are located 5′ to the 5′-end of the RNA transcript are referred to as “upstream sequences;” sequences on the DNA strand having the same sequence as the RNA and which are 3′ to the 3′ end of the coding RNA transcript are referred to as “downstream sequences.”
“cDNA” refers to a DNA that is complementary or identical to an mRNA, in either single stranded or double stranded form.
“Encoding” refers to the inherent property of specific sequences of nucleotides in a polynucleotide, such as a gene, a cDNA, or an mRNA, to serve as templates for synthesis of other polymers and macromolecules in biological processes having either a defined sequence of nucleotides (for example, rRNA, tRNA and mRNA) or a defined sequence of amino acids and the biological properties resulting therefrom. Thus, a gene encodes a protein if transcription and translation of mRNA produced by that gene produces the protein in a cell or other biological system. Both the coding strand, the nucleotide sequence of which is identical to the mRNA sequence and is usually provided in sequence listings, and non-coding strand, used as the template for transcription, of a gene or cDNA can be referred to as encoding the protein or other product of that gene or cDNA. Unless otherwise specified, a “nucleotide sequence encoding an amino acid sequence” includes all nucleotide sequences that are degenerate versions of each other and that encode the same amino acid sequence. Nucleotide sequences that encode proteins and RNA may include introns.
“Recombinant nucleic acid” refers to a nucleic acid having nucleotide sequences that are not naturally joined together. This includes nucleic acid vectors comprising an amplified or assembled nucleic acid which can be used to transform a suitable host cell. A host cell that comprises the recombinant nucleic acid is referred to as a “recombinant host cell.” The gene is then expressed in the recombinant host cell to produce, such as a “recombinant polypeptide.” A recombinant nucleic acid may serve a non-coding function (such as a promoter, origin of replication, ribosome-binding site, etc.) as well.
A first sequence is an “antisense” with respect to a second sequence if a polynucleotide whose sequence is the first sequence specifically hybridizes with a polynucleotide whose sequence is the second sequence.
Terms used to describe sequence relationships between two or more nucleotide sequences or amino acid sequences include “reference sequence,” “selected from,” “comparison window,” “identical,” “percentage of sequence identity,” “substantially identical,” “complementary,” and “substantially complementary.”
For sequence comparison of nucleic acid sequences and amino acids sequences, typically one sequence acts as a reference sequence, to which test sequences are compared. When using a sequence comparison algorithm, test and reference sequences are entered into a computer, subsequence coordinates are designated, if necessary, and sequence algorithm program parameters are designated. Default program parameters are used. Methods of alignment of sequences for comparison are well known in the art. Optimal alignment of sequences for comparison can be conducted, for example, by the local homology algorithm of Smith & Waterman, Adv. Appl. Math. 2:482, 1981, by the homology alignment algorithm of Needleman & Wunsch, J. Mol. Biol. 48:443, 1970, by the search for similarity method of Pearson & Lipman, Proc. Nat'l. Acad. Sci. USA 85:2444, 1988, by computerized implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Dr., Madison, Wis.), or by manual alignment and visual inspection (see for example, Current Protocols in Molecular Biology (Ausubel et al., eds 1995 supplement)).
One example of a useful algorithm is PILEUP, PILEUP uses a simplification of the progressive alignment method of Feng & Doolittle, J. Mol. Evol. 35:351-360, 1987. The method used is similar to the method described by Higgins & Sharp, CABIOS 5:151-153, 1989. Using PILEUP, a reference sequence is compared to other test sequences to determine the percent sequence identity relationship using the following parameters: default gap weight (3.00), default gap length weight (0.10), and weighted end gaps. PILEUP can be obtained from the GCG sequence analysis software package, such as version 7.0 (Devereaux et al., Nuc. Acids Res. 12:387-395, 1984.
Another example of algorithms that are suitable for determining percent sequence identity and sequence similarity are the BLAST and the BLAST 2.0 algorithm, which are described in Altschul et al., J. Mol. Biol. 215:403-410, 1990 and Altschul et al., Nucleic Acids Res. 25:3389-3402, 1977. Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information (ncbi.nlm.nih.gov). The BLASTN program (for nucleotide sequences) uses as defaults a word length (W) of 11, alignments (B) of 50, expectation (E) of 10, M=5, N=−4, and a comparison of both strands. The BLASTP program (for amino acid sequences) uses as defaults a word length (W) of 3, and expectation (E) of 10, and the BLOSUM62 scoring matrix (see Henikoff & Henikoff, Proc. Natl. Acad. Sci. USA 89:10915, 1989).
Another indicia of sequence similarity between two nucleic acids is the ability to hybridize. The more similar are the sequences of the two nucleic acids, the more stringent the conditions at which they will hybridize. The stringency of hybridization conditions are sequence-dependent and are different under different environmental parameters. Thus, hybridization conditions resulting in particular degrees of stringency will vary depending upon the nature of the hybridization method of choice and the composition and length of the hybridizing nucleic acid sequences. Generally, the temperature of hybridization and the ionic strength (especially the Na+ and/or Mg++ concentration) of the hybridization buffer will determine the stringency of hybridization, though wash times also influence stringency. Generally, stringent conditions are selected to be about 5° C. to 20° C. lower than the thermal melting point (Tm) for the specific sequence at a defined ionic strength and pH. The Tm is the temperature (under defined ionic strength and pH) at which 50% of the target sequence hybridizes to a perfectly matched probe. Conditions for nucleic acid hybridization and calculation of stringencies can be found, for example, in Sambrook et al., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 2001; Tijssen, Hybridization With Nucleic Acid Probes, Part I: Theory and Nucleic Acid Preparation, Laboratory Techniques in Biochemistry and Molecular Biology, Elsevier Science Ltd., NY, N.Y., 1993 and Ausubel et al. Short Protocols in Molecular Biology, 4th ed., John Wiley & Sons, Inc., 1999.
“Stringent conditions” encompass conditions under which hybridization will only occur if there is less than 25% mismatch between the hybridization molecule and the target sequence. “Stringent conditions” may be broken down into particular levels of stringency for more precise definition. Thus, as used herein, “moderate stringency” conditions are those under which molecules with more than 25% sequence mismatch will not hybridize; conditions of “medium stringency” are those under which molecules with more than 15% mismatch will not hybridize, and conditions of “high stringency” are those under which sequences with more than 10% mismatch will not hybridize. Conditions of “very high stringency” are those under which sequences with more than 6% mismatch will not hybridize. In contrast nucleic acids that hybridize under “low stringency conditions include those with much less sequence identity, or with sequence identity over only short subsequences of the nucleic acid. For example, a nucleic acid construct can include a polynucleotide sequence that hybridizes under high stringency or very high stringency, or even higher stringency conditions to a polynucleotide sequence that encodes SEQ ID NO: 1.
Operably linked: A first nucleic acid sequence is operably linked with a second nucleic acid sequence when the first nucleic acid sequence is placed in a functional relationship with the second nucleic acid sequence. For instance, a promoter is operably linked to a coding sequence if the promoter affects the transcription or expression of the coding sequence. Generally, operably linked DNA sequences are contiguous and, where necessary to join two protein-coding regions, in the same reading frame.
Peptide Modifications: The present disclosure includes mutant gp120 peptides, as well as synthetic embodiments. In addition, analogues (non-peptide organic molecules), derivatives (chemically functionalized peptide molecules obtained starting with the disclosed peptide sequences) and variants (homologs) of gp120 can be utilized in the methods described herein. The peptides disclosed herein include a sequence of amino acids that can be either L- and/or D-amino acids, naturally occurring and otherwise.
Peptides can be modified by a variety of chemical techniques to produce derivatives having essentially the same activity as the unmodified peptides, and optionally having other desirable properties. For example, carboxylic acid groups of the protein, whether carboxyl-terminal or side chain, may be provided in the form of a salt of a pharmaceutically-acceptable cation or esterified to form a C1-C16 ester, or converted to an amide of formula NR1R2 wherein R1 and R2 are each independently H or C1-C16 alkyl, or combined to form a heterocyclic ring, such as a 5- or 6-membered ring. Amino groups of the peptide, whether amino-terminal or side chain, may be in the form of a pharmaceutically-acceptable acid addition salt, such as the HCl, HBr, acetic, benzoic, toluene sulfonic, maleic, tartaric and other organic salts, or may be modified to C1-C16 alkyl or dialkyl amino or further converted to an amide.
Hydroxyl groups of the peptide side chains can be converted to C1-C16 alkoxy or to a C1-C16 ester using well-recognized techniques. Phenyl and phenolic rings of the peptide side chains can be substituted with one or more halogen atoms, such as F, Cl, Br or I, or with C1-C16 alkyl, C1-C16 alkoxy, carboxylic acids and esters thereof, or amides of such carboxylic acids. Methylene groups of the peptide side chains can be extended to homologous C2-C4 alkylenes. Thiols can be protected with any one of a number of well-recognized protecting groups, such as acetamide groups. Those skilled in the art will also recognize methods for introducing cyclic structures into the peptides of this disclosure to select and provide conformational constraints to the structure that result in enhanced stability. For example, a C- or N-terminal cysteine can be added to the peptide, so that when oxidized the peptide will contain a disulfide bond, generating a cyclic peptide. Other peptide cyclizing methods include the formation of thioethers and carboxyl- and amino-terminal amides and esters.
Peptidomimetic and organomimetic embodiments are also within the scope of the present disclosure, whereby the three-dimensional arrangement of the chemical constituents of such peptido- and organomimetics mimic the three-dimensional arrangement of the peptide backbone and component amino acid side chains, resulting in such peptido- and organomimetics of the proteins of this disclosure. For computer modeling applications, a pharmacophore is an idealized, three-dimensional definition of the structural requirements for biological activity. Peptido- and organomimetics can be designed to fit each pharmacophore with current computer modeling software (using computer assisted drug design or CADD). See Walters, “Computer-Assisted Modeling of Drugs”, in Klegerman & Groves, eds., 1993, Pharmaceutical Biotechnology, Interpharm Press: Buffalo Grove, Ill., pp. 165-174 and Principles of Pharmacology Munson (ed.) 1995, Ch. 102, for descriptions of techniques used in CADD. Also included within the scope of the disclosure are mimetics prepared using such techniques. In one example, a mimetic mimics the antigenic activity generated by gp120 a mutant, a variant, fragment, or fusion thereof.
Pharmaceutical agent: A chemical compound or composition capable of inducing a desired therapeutic or prophylactic effect when properly administered to a subject or a cell. “Incubating” includes a sufficient amount of time for a drug to interact with a cell. “Contacting” includes incubating a drug in solid or in liquid form with a cell. An “anti-viral agent” or “anti-viral drug” is an agent that specifically inhibits a virus from replicating or infecting cells. Similarly, an “anti-retroviral agent” is an agent that specifically inhibits a retrovirus from replicating or infecting cells.
A “therapeutically effective amount” is a quantity of a chemical composition or an anti-viral agent sufficient to achieve a desired effect in a subject being treated. For instance, this can be the amount necessary to inhibit viral replication or to measurably alter outward symptoms of the viral infection, such as increase of T cell counts in the case of an HIV-1 infection. In general, this amount will be sufficient to measurably inhibit virus (for example, HIV) replication or infectivity. When administered to a subject, a dosage will generally be used that will achieve target tissue concentrations (for example, in lymphocytes) that has been shown to achieve in vitro inhibition of viral replication.
Pharmaceutically acceptable carriers: The pharmaceutically acceptable carriers of use are conventional. Remington's Pharmaceutical Sciences, by E. W. Martin, Mack Publishing Co., Easton, Pa., 15th Edition, 1975, describes compositions and formulations suitable for pharmaceutical delivery of the fusion proteins herein disclosed.
In general, the nature of the carrier will depend on the particular mode of administration being employed. For instance, parenteral formulations usually comprise injectable fluids that include pharmaceutically and physiologically acceptable fluids such as water, physiological saline, balanced salt solutions, aqueous dextrose, glycerol or the like as a vehicle. For solid compositions (such as powder, pill, tablet, or capsule forms), conventional non-toxic solid carriers can include, for example, pharmaceutical grades of mannitol, lactose, starch, or magnesium stearate. In addition to biologically neutral carriers, pharmaceutical compositions to be administered can contain minor amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, preservatives, and pH buffering agents and the like, for example sodium acetate or sorbitan monolaurate.
Polypeptide: Any chain of amino acids, regardless of length or post-translational modification (such as glycosylation or phosphorylation). “Polypeptide” applies to amino acid polymers to naturally occurring amino acid polymers and non-naturally occurring amino acid polymer as well as in which one or more amino acid residue is a non-natural amino acid, for example a artificial chemical mimetic of a corresponding naturally occurring amino acid. In one embodiment, the polypeptide is a gp120 polypeptide, such as a stabilized gp120. A “residue” refers to an amino acid or amino acid mimetic incorporated in a polypeptide by an amide bond or amide bond mimetic. A polypeptide has an amino terminal (N-terminal) end and a carboxy terminal (C-terminal) end. “Polypeptide” is used interchangeably with peptide or protein, and is used interchangeably herein to refer to a polymer of amino acid residues.
Protein core: The protein core refers to the interior of a folded protein, which is substantially free of solvent exposure, such as solvent in the form of water molecules in solution. Typically, the protein core is predominately composed of hydrophobic or apolar amino acids. In some examples, a protein core may contain charged amino acids, for example aspartic acid, glutamic acid, arginine, and/or lysine. The inclusion of uncompensated charged amino acids (a compensated charged amino can be in the form of a salt bridge) in the protein core can lead to a destabilized protein. That is, a protein with a lower Tm then a similar protein without an uncompensated charged amino acid in the protein core. In other examples, a protein core may have a cavity with in the protein core. Cavities are essentially voids within a folded protein where amino acids or amino acid side chains are not present. Such cavities can also destabilize a protein relative to a similar protein without a cavity. Thus, when creating a stabilized form of a protein, for example a stabilized form of gp120, it may be advantageous to substitute amino acid residues within the core in order to fill cavities present in the wild-type protein.
Purified: The term purified does not require absolute purity; rather, it is intended as a relative term. Thus, for example, a purified protein is one in which the protein is more enriched than the protein is in its natural environment within a cell. Preferably, a preparation is purified such that the protein represents at least 50% of the protein content of the preparation.
The gp120 polypeptides disclosed herein, or antibodies that specifically bind gp120, can be purified by any of the means known in the art. See for example Guide to Protein Purification, ed. Deutscher, Meth. Enzymol. 185, Academic Press, San Diego, 1990; and Scopes, Protein Purification: Principles and Practice, Springer Verlag, New York, 1982. Substantial purification denotes purification from other proteins or cellular components. A substantially purified protein is at least 60%, 70%, 80%, 90%, 95% or 98% pure. Thus, in one specific, non-limiting example, a substantially purified protein is 90% free of other proteins or cellular components.
Space Group: The arrangement of symmetry elements of a crystal.
Structure coordinates: Mathematical coordinates derived from mathematical equations related to the patterns obtained on diffraction of a monochromatic beam of X-rays by the atoms (scattering centers) such as a gp120, a gp120:CD4 complex, a gp120:antibody complex, or combinations thereof in a crystal in crystal form. The diffraction data are used to calculate an electron density map of the repeating unit of the crystal. The electron density maps are used to establish the positions of the individual atoms within the unit cell of the crystal. In one example, the term “structure coordinates” refers to Cartesian coordinates derived from mathematical equations related to the patterns obtained on diffraction of a monochromatic beam of X-rays, such as by the atoms of a stabilized form of gp120 in crystal form.
Atomic coordinate data, such as that in Table 1 and Table 2 lists each atom by a unique number (column 2); the atom name in the context of the residue to which it belongs (column 3), for example CA refers to the alpha carbon of the peptide backbone (detailed descriptions of the atom identifiers for each residue can be found for example in Creighton, Proteins, Structures and Molecular Properties, W.H. Freeman & Co., New York, 1993); the amino acid residue in which the atom is located (column 4); the chain identifier (column 4′) which may or may not be included, the number of the residue (column 5); the coordinates (for example, X, Y, Z) which define with respect to the crystallographic axes the atomic position (in Å) of the respective atom (columns 6, 7, and 8); the occupancy of the atom in the respective position (column 9); the “B-factor”, which is the isotropic displacement parameter (in Å2) and accounts for movement of the atom around its atomic center (column 10).
Those of ordinary skill in the art understand that a set of structure coordinates determined by X-ray crystallography is not without standard error. For the purpose of this disclosure, any set of structure coordinates for a stabilized form of gp120 or a gp120 with an extended V3 loop that have a root mean square deviation of protein backbone atoms (N, Cα, C and 0) of less than about 1.0 Angstroms when superimposed, such as about 0.75, or about 0.5, or about 0.25 Angstroms, using backbone atoms, on the structure coordinates listed in Table 1 or Table 2 shall (in the absence of a explicit statement to the contrary) be considered identical.
Subject: Living multi-cellular vertebrate organisms, a category that includes both human and veterinary subjects, including human and non-human mammals.
T Cell: A white blood cell critical to the immune response. T cells include, but are not limited to, CD4+ T cells and CD8+ T cells. A CD4+ T lymphocyte is an immune cell that carries a marker on its surface known as “cluster of differentiation 4” (CD4). These cells, also known as helper T cells, help orchestrate the immune response, including antibody responses as well as killer T cell responses. CD8+ T cells carry the “cluster of differentiation 8” (CD8) marker. In one embodiment, a CD8 T cells is a cytotoxic T lymphocytes. In another embodiment, a CD8 cell is a suppressor T cell.
Therapeutic agent: Used in a generic sense, it includes treating agents, prophylactic agents, and replacement agents.
Tm: The temperature at which a change of state occurs. For example, the temperature at which gp120 undergoes a transition from the folded form to the unfolded form. Essentially this is the temperature at which the structure melts away. Stabilized gp120 has a higher Tm than native gp120. Another example would be the temperature at which a DNA duplex melts.
Transformed: A transformed cell is a cell into which has been introduced a nucleic acid molecule by molecular biology techniques. As used herein, the term transformation encompasses all techniques by which a nucleic acid molecule might be introduced into such a cell, including transfection with viral vectors, transformation with plasmid vectors, and introduction of DNA by electroporation, lipofection, and particle gun acceleration.
Unit Cell: The smallest building block of a crystal. The entire volume of a crystal may be constructed by regular assembly of such blocks. Each unit cell comprises a complete representation of the unit of pattern, the repetition of which builds produces a crystal lattice
Vector: A nucleic acid molecule as introduced into a host cell, thereby producing a transformed host cell. Recombinant DNA vectors are vectors having recombinant DNA. A vector can include nucleic acid sequences that permit it to replicate in a host cell, such as an origin of replication. A vector can also include one or more selectable marker genes and other genetic elements known in the art. Viral vectors are recombinant DNA vectors having at least some nucleic acid sequences derived from one or more viruses.
Virus: Microscopic infectious organism that reproduces inside living cells. A virus consists essentially of a core of a single nucleic acid surrounded by a protein coat, and has the ability to replicate only inside a living cell. “Viral replication” is the production of additional virus by the occurrence of at least one viral life cycle. A virus may subvert the host cells' normal functions, causing the cell to behave in a manner determined by the virus. For example, a viral infection may result in a cell producing a cytokine, or responding to a cytokine, when the uninfected cell does not normally do so.
“Retroviruses” are RNA viruses wherein the viral genome is RNA. When a host cell is infected with a retrovirus, the genomic RNA is reverse transcribed into a DNA intermediate which is integrated very efficiently into the chromosomal DNA of infected cells. The integrated DNA intermediate is referred to as a provirus. The term “lentivirus” is used in its conventional sense to describe a genus of viruses containing reverse transcriptase. The lentiviruses include the “immunodeficiency viruses” which include human immunodeficiency virus (HIV) type 1 and type 2 (HIV-1 and HIV-2), simian immunodeficiency virus (SIV), and feline immunodeficiency virus (FIV).
HIV-1 is a retrovirus that causes immunosuppression in humans (HIV disease), and leads to a disease complex known as the acquired immunodeficiency syndrome (AIDS). “HIV disease” refers to a well-recognized constellation of signs and symptoms (including the development of opportunistic infections) in persons who are infected by an HIV virus, as determined by antibody or western blot studies. Laboratory findings associated with this disease are a progressive decline in T cells.
X5: An antibody that bonds a conformation of gp120 induced by the binding of CD4. Antibodies that bind to gp120 in a conformation induced by CD4 binding are termed CD4i antibodies.
ΔS: The change in entropy, such as the change in entropy upon the association of gp120 and CD4 or an antibody or antibody fragment, for example X5.
ΔH: The change in the enthalpy, such as the change enthalpy upon the association of gp120 and CD4 or an antibody.
II. Overview of Several Embodiments
Provided herein in various embodiments are gp120 polypeptides, which are useful to induce immunogenic response in vertebrate animals (such as mammals, for example primates, such as humans) to lentivirus, such as SIV or HIV (for example HIV-I and HIV-II).
In several embodiments, the gp120 polypeptides are stabilized in a CD4 bound conformation. In several disclosed examples, the gp120 polypeptides are stabilized by modification. In certain examples, these modifications can be the introduction of a plurality of non-naturally occurring cross-linking cysteine residues. In certain examples, the modification can be the introduction of at least one amino acid substitution in the protein core of gp120.
In several disclosed examples, cysteines are introduced into the gp120 polypeptide at position 96, 109, 123, 231, 267, 275, 428, 431 or in combinations thereof. In some examples of gp120 polypeptides disclosed herein, the plurality of non-naturally occurring cross-linking cysteine residues are defined by the interaction and crosslinking of at least one of residue pairs 96 and 275; 109 and 428; 123 and 431; and 231 and 267. In some embodiments, all of the residue pairs 96 and 275; 109 and 428; 123 and 431; and 231 and 267 are crosslinked.
In some embodiments, the stabilized gp120 polypeptide contains one or more amino acid substitutions in the protein core. In several examples, the substitution is made at position 95, 257, 375, 433, or a combination thereof. In specific examples, the substitution is a serine to tryptophan substitution at position 95, a threonine to serine substitution at position 257, a serine to tryptophan substitution at position 375, an alanine to methionine substitution at position 433, or a combination thereof.
In specific examples, the stabilized gp120 polypeptide includes the amino acid sequence set forth as SEQ ID NO: 1 or is encoded by one of SEQ ID NO: 4, 5, 6, 7, 8, 10, 11, 12, 13, and 14, 15, 16, 17, 18, or degenerate variants thereof. In still other embodiments, the stabilized gp120 contains a portion of the amino acid sequence set forth as SED ID NO: 1 or as encoded by any one of SEQ NOs:4-18, for example, a domain such as the outer domain, or a contiguous stretch of about 5 or more amino acids, such as about 6, about 7, about 8, about 9, about 10, about 15, about 20, about 25, or more amino acids.
In other examples, the gp120 polypeptide has the V3 loop in an extended conformation. In one example, the gp120 polypeptide with the V3 loop in an extended conformation contains the amino acid sequence set forth as SEQ ID NO: 2. In other embodiments, the gp120 polypeptide with an extended v3 loop contains a portion of the amino acid sequence set forth as SED ID NO: 2, for example, a domain such as the outer domain, or a contiguous stretch of about 5 or more amino acids, such as about 6, about 7, about 8, about 9, about 10, about 15, about 20, about 25, or more amino acids wherein the domain or contiguous stretch of amino acids includes a portion of the V3 loop.
Other embodiments are compositions containing a therapeutically effective amount of at least one gp120 polypeptide, such as a stabilized gp120 polypeptide (such as set forth as SEQ ID NO: 1 or as encoded by the nucleotide sequence set forth as one of SEQ ID NO: 4, 5, 6, 7, 8, 10, 11, 12, 13, 14 15, 16, 17, and 18, or a degenerate variant thereof) or a gp120 polypeptide with the V3 loop in an extended conformation, such as the amino acid sequence set forth as SEQ NO: 2. In some embodiments, the composition can contain pharmaceutically acceptable carriers, adjuvants, or combinations thereof.
This disclosure further provides methods for eliciting and/or enhancing an immune response in a subject (such as a primate subject, for example a human subject). In some embodiments, these methods involve administering to the subject a composition including a gp120 polypeptide as disclosed herein, for example a stabilized gp120 such as set forth as SEQ ID NO: 1 or as encoded by the nucleotide sequence set forth as one of SEQ ID NO: 4, 5, 6, 7, 8, 10, 11, 12, 13, 14 15, 16, 17, and 18, or a degenerate variant thereof. In some embodiments, these methods involve administering to the subject a composition including a gp120 polypeptide with an extended V3 loop such as set forth as SEQ ID NO: 2. In one specific, non-limiting example, the subject is infected with a lentivirus, for example SIV or HIV, such as HIV-1 or HIV-2. In some embodiments, the immune response is a B cell response, a T cell response, or a combination thereof.
In other embodiments, the subject is further administered a therapeutically effective amount of a monomeric or trimeric gp140 polypeptide, an unmodified monomeric or trimeric gp120 polypeptide, or a combination thereof.
Other embodiments of this disclosure are isolated polynucleotides (nucleic acid molecules) which encode the gp120 polypeptides described herein. Specific examples of such nucleic acid molecules contain nucleic acids encoding the amino acid sequence set forth as one of SEQ ID NO: 1 or 2, the nucleotide sequences set forth as one of SEQ ID NOs: 4-18, or degenerate variants thereof. In other embodiments, the isolated polynucleotides consist of nucleic acid molecules encoding the amino acid sequence set forth as one of SEQ ID NO: 1 or 2, the nucleotide sequences set forth as one of SEQ ID NOs: 4-18, or degenerate variants thereof. In certain embodiments, the nucleic acid encoding a gp120 polypeptide is operably linked to a promoter. Vectors comprising such polynucleotides are also disclosed, as are host cells transformed with such vectors.
Other embodiments are compositions containing a therapeutically effective amount of a polynucleotide containing a nucleic acid encoding a gp120 polypeptide disclosed herein. In certain embodiments, the nucleic acid encodes the amino acid sequence set forth as SEQ ID NO: 1 and 2. In other embodiments the nucleic acid contains the one of the nucleotide sequences set forth as SEQ ID NO: 4-18 or a degenerate variant thereof. In some embodiments, the composition can contain pharmaceutically acceptable carriers, adjuvants, or combinations thereof.
This disclosure further provides methods for eliciting and/or enhancing an immune response in a subject (such as a primate subject, for example a human subject). The methods involve administering to the subject a composition containing a nucleic acid encoding a gp120 polypeptide of this disclosure. In one specific, non-limiting example, the subject is infected with a lentivirus, for example SIV or HIV, such as HIV-1 or HIV-2. In some embodiments, the immune response is a B cell response, a T cell response, or a combination thereof.
In other embodiments, the subject is further administered a therapeutically effective amount of a plasmid vector expressing a polypeptide containing a monomeric or trimeric gp140 polypeptide, an unmodified monomeric or trimeric gp120 polypeptide; or combination thereof.
Also disclosed herein are methods for identifying an immunogen that induces an immune response to gp120, for example gp120 from a lentivirus, such as SIV or HIV such as HIV-1 or HIV-2. Typically the immune response is a B cell response, a T cell response, or a combination thereof. These methods involve using a three-dimensional structure of gp120 as defined by atomic coordinates set forth in Table 1, Table 2, or a portion thereof to design or select the immunogen, synthesizing the immunogen, immunizing a subject with the immunogen; and determining if an immune response to gp120 is induced in the subject. In some embodiments, the immunogen is designed from the gp120 amino acid sequence. In certain embodiments, the immunogen is designed or selected using a three-dimensional structure of gp120 as defined by atomic coordinates set forth in Table 1, Table 2, or a portion thereof and an amino acid sequence is assembled to provide an immunogen, for example by synthesizing the amino acid sequence or producing a nucleic acid encoding the immunogen. In other embodiments the is selected from a database of compounds or is designed de novo.
Also provided by this disclosure is a machine readable data storage medium including a data storage material encoded with machine readable data corresponding to the coordinates of a stabilized form of gp120 as defined by Table 1 or a portion thereof or a form of gp120 having an extended conformation of the V3 loop as defined by Table 2 or a portion thereof.
Also provided for are computer systems including data and a data processor, wherein the system forms a representation of the three-dimensional structure gp120 protein as defined by Table 1, Table 2, or a portion thereof, such as the atomic positions, surface, domain, or region of the gp120 polypeptide.
Also disclosed herein is the use of stabilized gp120 molecules as crystallization tools. A crystalline form of a stabilized gp120 also is disclosed, for example the crystalline form of gp120 as defined by the coordinates as given in Table 1, or with coordinates having a root mean square deviation therefrom, wherein the distance between the residues is less than about 0.75 Å. A crystalline form of a gp120 with an extended V3 loop also is disclosed, for example the crystalline form of gp120 as defined by the coordinates as given in Table 2, or with coordinates having a root mean square deviation therefrom, wherein the distance between the residues is less than about 0.75 Å.
III. gp120 Immunogens and Nucleic Acids Encoding gp120 Immunogens
The present disclosure relates to gp120 polypeptides and nucleic acids encoding these gp120 polypeptides. The gp120 polypeptides of this disclosure are capable of eliciting an immune response to a gp120 protein in a subject, such as a human subject. In some embodiments, the gp120 polypeptides of this disclosure are stabilized in a CD4 bound conformation.
Using a combination of atomic level structural information with biophysical techniques novel gp120 polypeptides were designed that are stabilized in the conformation substantially identical to the CD4 bound polypeptide. For example, the three-dimensional structure of the wild-type polypeptide was analyzed to determine where cysteine residues could be introduced such that they would form disulfide bonds in the folded molecule. This methodology is not specific to cysteine residues; other natural or non-natural amino acids could be used. In some embodiments, the stabilized gp120 has a Kd for CD4 of less than or equal to about 10 nM, such as less than or equal to about 5 nM, less than or equal to about 3 nM, or less than or equal to about 1 nM. In some embodiments the stabilized gp120 has −TΔS for CD4 binding of about less than or equal to 40 kcal/mol, such as about less than or equal to 30 kcal/mol, about less than or equal to 15 kcal/mol, or about less than or equal to 10 kcal/mol.
The stability of folded polypeptides can be measured using techniques such as thermal denaturation. The temperature of the unfolding transition (Tm) is an accepted measure of the stability of the folded polypeptide, where increases in Tm indicate an increase in the stability of the folded polypeptide. In some embodiments, the stabilized gp120 polypeptides has a Tm value greater than about 52° C., such as greater than about 53° C., greater than about 54° C. (such as 53.8° C.), greater than about 55° C., greater than about 56° C., greater than about 57° C., greater than about 58° C., or even greater than about 59° C.
In some embodiments, the stabilized gp120 polypeptides are stabilized by a plurality of non-naturally occurring cross-linking cysteine residues. By plurality it is meant that there are at least 2, such as at least 4, at least 6, or at least 8 cysteines introduced by mutation into a gp120 polypeptide, such that pairs of cysteines form at least 1, such as at least 2, at least 3, or at least 4 disulfide bonds. Each disulfide bond is formed by a pair of cysteines.
In some embodiments, the mutationally introduced cysteines are introduced into the gp120 polypeptide at positions 96, 109, 123, 231, 267, 275, 428, 431, or in a sub-combination thereof. In some examples of the stabilized gp120 polypeptides, the plurality of non-naturally occurring cross-linking cysteine residues are defined by the interaction of at least one of residue pairs 96 and 275; 109 and 428; 123 and 431; and 231 and 267. Thus, the stabilized gp120 polypeptides of this disclosure may have any combination of the crosslinked cysteines defined by the interaction of 96 and 275; 109 and 428; 123 and 431; and 231 and 267.
In some embodiments, the stabilized gp120 polypeptide contains one or more amino acid substitutions in the protein core. In several disclosed examples, the substitution is made at position 95, 257, 375, 433, or a combination thereof. Thus, a stabilized gp120 polypeptide may have one, two, three, or four substitutions in the protein core. In specific examples, the substitution is a serine to tryptophan substitution at position 95, a threonine to serine substitution at position 257, a serine to tryptophan substitution at position 375, an alanine to methionine substitution at position 433, or various combinations thereof.
In one embodiment, the stabilized gp120 polypeptide (new—9c) includes the amino acid sequence set forth as:
(SEQ ID NO: 1)
EVVLVNVTENFNWCKNDMVEQMHEDICSLWDQSLKPCVKLCPLAGATSVI
TQACPKVSFEPIPIHYCAPAGFAILKCNNKTFNGTGPCTNVSTVQCTHGI
RPVVSSQLLLNGSLAEEEVVIRSCNFTDNAKTIIVQLNTSVEINCTRPNN
GGSGSGGNMRQAHCNISRAKWNNTLKQIASKLREQFGNNKTIIFKQSSGG
DPEIVTHWFNCGGEFFYCNSTQLFNSTWFNSTWSTEGSNNTEGSDTITLP
CRIKQIINMWCKVCKAMYAPPISGQIRCSSNITGLLLTRDGGNSNNESEI
FRPGGGDMRDNWRSELYKYKVVKIE.
In other embodiments, the stabilized gp120 includes the amino acid sequence encoded by one of SEQ ID NO: 4, 5, 6, 7, 8, 10, 11, 12, 13, 14, 15, 16, 17, and 18, or degenerate variants thereof. In still other embodiments, the stabilized gp120 polypeptide consists of the amino acid sequence set forth as SEQ ID NO: 1 or as encoded by the nucleotide sequence set forth as one of SEQ ID NO: 4, 5, 6, 7, 8, 10, 11, 12, 13, 14 15, 16, 17, and 18, or a degenerate variant thereof. In some embodiments, a stabilized gp120 polypeptide is an immunogenic fragment of SEQ ID NO: 1 or as encoded by the nucleotide sequence set forth as one of SEQ ID NO: 4, 5, 6, 7, 8, 10, 11, 12, 13, 14 15, 16, 17, and 18, or a degenerate variant thereof, such that the immunogenic fragment is stabilized in a CD4 binding conformation. In some embodiments, the stabilized gp120 includes the outer-domain. In one example, the outer domain includes residues 255-421 and 436-474 of gp120. Thus, the outer domain can contain residues 109-246 and 261-299 of SEQ ID NO: 1, the amino acid sequence encoded by SEQ ID NO: 4-18 or a degenerate variant thereof. In some examples residues 246 and 261 are covalently linked, for example by a peptide linker. In some examples, the peptide linker is residues 247-260 of SEQ ID NO: 1, the amino acid sequence encoded by SEQ ID NO: 4-18 or a degenerate variant thereof. Ideally the linker should be of sufficient length such that the folded protein is a conformation that can be bound by CD4. In some embodiments, the linker is a peptide linker and the peptide linker is about 2 to about 20 amino acids in length, such as about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 10, about 12, about 15, or about 20 amino acids in length. In some embodiments, the immunogenic fragment of gp120 consists of residues 109-246 and 261-299, and a linker. In some embodiments the linker does not contain a sequence form gp120.
In other embodiments, the stabilized gp120 fragment is truncated on the carboxy terminal end. For example, the carboxy terminal end can be truncated to about amino acid residue 433. In addition, portions of the amino terminus of gp120 can also be eliminated from the stabilized gp120 fragment. The truncated gp120 sequence can be free from the carboxy terminus through amino acid residue 95. In one embodiment, the truncated gp120 sequence is free from the amino terminus of gp120 through residue 95 and residue 433 through the carboxy terminus of gp120. Thus, in some embodiments the stabilized gp120 contains a portion of the amino acid sequence set forth as SEQ ID NO: 1 or as encoded by any one of SED NOs:4-18.
In other embodiments, the gp120 polypeptide has the V3 loop in an extended conformation. An exemplary sequence of a gp120 with an extended loop is set forth as:
(SEQ ID NO: 2)
GARSEVVLENVTEHFNMWKNDMVEQMQEDIISLWDQSLKPCVKLTPLCVG
AGSCDTSVITQACPKISFEPIPIHYCAPAGFAILKCNDKTFNGKGPCKNV
STVQCTHGIRPVVSTQLLLNGSLAEEEVVIRSDNFTNNAKTIIVQLKESV
EINCTRPNQNTRKSIHIGPGRAFYTTGEIIGDIRQAHCNISRAKWNDTLK
QIVIKLREQFENKTIVFNHSSGGDPEIVMHSFNCGGEFFYCNSAQLFNST
WNNNTEGSNNTEGNTITLPCRIKQIINMWQEVGKAMYAPPIRGQIRCSSN
ITGLLLTRDGGINENGTEIFRPGGGDMRDNWRSELYKYKVVKIE.
Thus, a gp120 polypeptide with an extended V3 loop can contain the amino acid sequence set forth as SEQ ID NO: 2 or a fragment thereof. In one example, the gp120 polypeptide with the V3 loop in an extended conformation consists of the amino acid sequence set forth as SEQ ID NO: 2 or a fragment thereof. In still other embodiments, the gp120 polypeptide with an extended V3 loop contains a portion of the amino acid sequence set forth as SED ID NO: 2. In some embodiments, the stabilized gp120 includes the outer-domain. In one example, the outer domain includes residues 255-421 and 436-474 of gp120. Thus, the outer domain can include residues 109-246 and 261-299 of SEQ ID NO: 2.
In other embodiments, the gp120 polypeptide has the V3 loop in an extended conformation is truncated on the carboxy terminal end. For example, the carboxy terminal end can be truncated to about amino acid residue 433. In addition, portions of the amino terminus of gp120 can also be eliminated from the gp120 polypeptide has the V3 loop in an extended conformation fragment. The truncated gp120 sequence can be free from the carboxy terminus through amino acid residue 95. In one embodiment, the truncated gp120 sequence is free from the amino terminus of gp120 through residue 95 and residue 433 through the carboxy terminus of gp120. Thus, in some embodiments the gp120 polypeptide has the V3 loop in an extended conformation contains a portion of the amino acid sequence set forth as SEQ ID NO: 2.
In other embodiments, the gp120 polypeptide has an amino acid sequence least 90% identical to SEQ ID NO: 1, SEQ ID NO: 2, or the amino acid sequence encoded by any one of SEQ ID NO: 4-18, for example a polypeptide that has about 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or even higher sequence identity to SEQ ID NO: 1, SEQ ID NO: 2, or the amino acid sequence encoded by any one of SEQ ID NO: 4-18.
The immunogenic gp120 polypeptides or immunogenic fragments of the gp120 polypeptides disclosed herein can be chemically synthesized by standard methods, or can be produced recombinantly. An exemplary process for polypeptide production is described in Lu et al., Federation of European Biochemical Societies Letters. 429:31-35, 1998. They can also be isolated by methods including preparative chromatography and immunological separations.
In other embodiments, fusion proteins are provided including a first and second polypeptide moiety in which one of the protein moieties includes an amino acid sequence as set forth in SEQ ID NO: 1 or 2, or a fragment thereof. In other embodiments, fusion proteins are provided comprising a first and second polypeptide moiety in which one of the protein moieties includes an amino acid sequence encoded by one of the nucleotide sequences as set forth as SEQ ID NO: 4-18, or a fragment thereof. The other moiety is a heterologous protein such as can be a carrier protein and/or an immunogenic protein. Such fusions also are useful to evoke an immune response against gp120. In certain embodiments the gp120 polypeptides disclosed herein are co-valent or non-covalent addition of TLR ligands or dendritic cell or B cell targeting moieties.
A gp120 polypeptide can be covalently linked to a carrier, which is an immunogenic macromolecule to which an antigenic molecule can be bound. When bound to a carrier, the bound polypeptide becomes more immunogenic. Carriers are chosen to increase the immunogenicity of the bound molecule and/or to elicit higher titers of antibodies against the carrier which are diagnostically, analytically, and/or therapeutically beneficial. Covalent linking of a molecule to a carrier can confer enhanced immunogenicity and T cell dependence (see Pozsgay et al., PNAS 96:5194-97, 1999; Lee et al., J. Immunol. 116:1711-18, 1976; Dintzis et al., PNAS 73:3671-75, 1976). Useful carriers include polymeric carriers, which can be natural (for example, polysaccharides, polypeptides or proteins from bacteria or viruses), semi-synthetic or synthetic materials containing one or more functional groups to which a reactant moiety can be attached. Bacterial products and viral proteins (such as hepatitis B surface antigen and core antigen) can also be used as carriers, as well as proteins from higher organisms such as keyhole limpet hemocyanin, horseshoe crab hemocyanin, edestin, mammalian serum albumins, and mammalian immunoglobulins. Additional bacterial products for use as carriers include bacterial wall proteins and other products (for example, streptococcal or staphylococcal cell walls and lipopolysaccharide (LPS)).
Most antigenic epitopes of HIV proteins are relatively small in size, such as about 5 to 100 amino acids in size, for example about 5, about 6, about 7, about 8, about 9, about 10, about 15, about 20, about 25, about 30, about 40, about 50, about 60, about 70, about 80, about 90, or about 100. Thus, fragments (for example, epitopes or other antigenic fragments) of a gp120 polypeptide, such as any of the gp120 polypeptides described herein or a fragment thereof, can be used as an immunogen.
In some embodiments, the disclosed gp120 polypeptides are modified by glycosylation, for example by N-linked glycans. Thus, the immune response can be focused on a region interest of a gp120 polypeptide by masking other regions with non-immunogenic glycans. Glycosylation sites can be introduced into the gp120 polypeptides by site directed mutagenesis. This straggly can be utilized to focus the immune response to regions of interest in the gp120 polypeptide, for example the CD4 binding site or the binding site for a neutralizing antibody, for example a the b12 antibody. Examples of glycan masking can be found in Pantophlet and Burton, Trends Mol Med. 9(11):468-73, 2003, which is incorporated by reference herein in its entirety.
Another strategy to focus the immune response on the CD4 binding region or b12 epitope region is to use SIV and HIVgp120 core glycoproteins (such as the stabilized gp120 polypeptides disclosed herein) that possess an endogenous CD4 binding site or to scaffold the heterologous HIV-1 CD4 binding region onto cores derived from selected SIV or HIV-2 strains. The gp120 core can be derived from the envelope glycoproteins of letivius, for example SIV such as SIV mac239 and HIV, such as HIV-2 7132A. The residues required for CD4BS antibody recognition, for example the site of b12 binding, are transplanted by site-directed mutagenesis of the appropriate codon-optimized plasmid sequences. In some embodiments, extra N-glycans are added to these cores to eliminate the elicitation of non-cross reactive antibodies directed against regions outside the antibody binding site, for example the binding site of a neutralizing antibody such as CD4BS antibody.
The present disclosure concerns nucleic acid constructs including polynucleotide sequences that encode antigenic gp120 polypeptides of HIV-1. These polynucleotides include DNA, cDNA and RNA sequences which encode the polypeptide of interest.
Methods for the manipulation and insertion of the nucleic acids of this disclosure into vectors are well known in the (see for example, Sambrook et al., Molecular Cloning, a Laboratory Manual, 2d edition, Cold Spring Harbor Press, Cold Spring Harbor, N.Y., 1989, and Ausubel et al., Current Protocols in Molecular Biology, Greene Publishing Associates and John Wiley & Sons, New York, N.Y., 1994).
Typically, the nucleic acid constructs encoding the gp120 polypeptides of this disclosure are plasmids. However, other vectors (for example, viral vectors, phage, cosmids, etc.) can be utilized to replicate the nucleic acids. In the context of this disclosure, the nucleic acid constructs typically are expression vectors that contain a promoter sequence which facilitates the efficient transcription of the inserted genetic sequence of the host. The expression vector typically contains an origin of replication, a promoter, as well as specific nucleic acid sequences that allow phenotypic selection of the transformed cells.
More generally, polynucleotide sequences encoding the gp120 polypeptides of this disclosure can be operably linked to any promoter and/or enhancer that is capable of driving expression of the nucleic acid following introduction into a host cell. A promoter is an array of nucleic acid control sequences that directs transcription of a nucleic acid. A promoter includes necessary nucleic acid sequences (which can be) near the start site of transcription, such as in the case of a polymerase II type promoter (a TATA element). A promoter also can include distal enhancer or repressor elements which can be located as much as several thousand base pairs from the start site of transcription. Both constitutive and inducible promoters are included (see, for example, Bitter et al., Methods in Enzymology 153:516-544, 1987).
To produce such nucleic acid constructs, polynucleotide sequences encoding gp120 polypeptides are inserted into a suitable expression vector, such as a plasmid expression vector. Procedures for producing polynucleotide sequences encoding gp120 polypeptides and for manipulating them in vitro are well known to those of skill in the art, and can be found, for example in Sambrook and Ausubel, supra.
In addition to the polynucleotide sequences encoding the polypeptides set forth as SEQ ID NOs:1-2 disclosed herein and nucleic acids encoding gp120 polypeptides as set forth as SEQ ID NOs:4-18 as disclosed herein, the nucleic acid constructs can include variant polynucleotide sequences that encode polypeptides that are substantially similar to SEQ ID NOs: 1-2 and nucleic acids encoding gp120 polypeptides as set forth as SEQ ID NOs: 4-18. Similarly, the nucleic acid constructs can include polynucleotides that encode chimeric polypeptides, for example fusion proteins. For enhanced immunogenicity, it may be advantageous to include the sequence encoding for heterologous T helper sequences derived from HIV or other heterologous sources.
The similarity between amino acid (and polynucleotide) sequences is expressed in terms of the similarity between the sequences, otherwise referred to as sequence identity. Sequence identity is frequently measured in terms of percentage identity (or similarity); the higher the percentage, the more similar are the primary structures of the two sequences. In general, the more similar the primary structures of two amino acid sequences, the more similar are the higher order structures resulting from folding and assembly. Thus, the nucleic acid constructs can include polynucleotides that encode polypeptides that are at least about 90%, or 95%, 98%, or 99% identical to one of SEQ ID NOs: 1-2 with respect to amino acid sequence, or that have at least about 90%, 95%, 98%, or 99% sequence identity to one or more of SEQ ID NOs: 4-18 and/or that differ from one of these sequences by the substitution of degenerate codons.
DNA sequences encoding an immunogenic gp120 polypeptide can be expressed in vitro by DNA transfer into a suitable host cell. The cell may be prokaryotic or eukaryotic. The term also includes any progeny of the subject host cell. It is understood that all progeny may not be identical to the parental cell since there may be mutations that occur during replication. Methods of stable transfer, meaning that the foreign DNA is continuously maintained in the host, are known in the art.
The polynucleotide sequences encoding an immunogenic gp120 polypeptide can be inserted into an expression vector including, but not limited to, a plasmid, virus or other vehicle that can be manipulated to allow insertion or incorporation of sequences and can be expressed in either prokaryotes or eukaryotes. Hosts can include microbial, yeast, insect, and mammalian organisms. Methods of expressing DNA sequences having eukaryotic or viral sequences in prokaryotes are well known in the art. Biologically functional viral and plasmid DNA vectors capable of expression and replication in a host are known in the art.
Transformation of a host cell with recombinant DNA can be carried out by conventional techniques that are well known to those of ordinary skill in the art. Where the host is prokaryotic, such as E. coli, competent cells which are capable of DNA uptake can be prepared from cells harvested after exponential growth phase and subsequently treated by the CaCl2 method using procedures well known in the art. Alternatively, MgCl2 or RbCl can be used. Transformation can also be performed after forming a protoplast of the host cell if desired, or by electroporation.
When the host is a eukaryote, such methods of transfection of DNA as calcium phosphate coprecipitates, conventional mechanical procedures such as microinjection, electroporation, insertion of a plasmid encased in liposomes, or virus vectors can be used. Eukaryotic cells can also be co-transformed with polynucleotide sequences encoding an immunogenic gp120 polypeptide, and a second foreign DNA molecule encoding a selectable phenotype, such as the herpes simplex thymidine kinase gene. Another method is to use a eukaryotic viral vector, such as simian virus 40 (SV40) or bovine papilloma virus, to transiently infect or transform eukaryotic cells and express the protein (see for example, Eukaiyotic Viral Vectors, Cold Spring Harbor Laboratory, Gluzman ed., 1982).
IV. Immunogenic Compositions and Therapeutic Methods
Any of the gp120 polypeptides and nucleic acid molecules encoding the gp120 polypeptides disclosed herein can be used as immunogens, or to produce immunogens to elicit an immune response (immunogenic compositions) to gp120 such as to a gp120 expressing virus, for example to reduce HIV-1 infection or a symptom of HIV-1 infection. Following administration of a therapeutically effective amount of the disclosed therapeutic compositions, the subject can be monitored for HIV-1 infection, symptoms associated with HIV-1 infection, or both. Disclosed hereinare methods of administering the therapeutic molecules disclosed herein (such as gp120 polypeptides and nucleic acids encoding gp120 polypeptides) to reduce HIV-1 infection. In several examples, a therapeutically effective amount of a gp120 polypeptide including SEQ ID NO: 1, a therapeutically effective amount of a gp120 polypeptide including SEQ ID NO: 2, a therapeutically effective amount of a gp120 polypeptide encoded by one of SEQ ID NOs: 4-18 or a degenerate variant thereof, or a combination thereof is administered to a subject.
In certain embodiments, the immunogenic composition includes an adjuvant. An adjuvant can be a suspension of minerals, such as alum, aluminum hydroxide, aluminum phosphate, on which antigen is adsorbed; or water-in-oil emulsion in which antigen solution is emulsified in oil (MF-59, Freund's incomplete adjuvant), sometimes with the inclusion of killed mycobacteria (Freund's complete adjuvant) to further enhance antigenicity (inhibits degradation of antigen and/or causes influx of macrophages). In one embodiment, the adjuvant is a mixture of stabilizing detergents, micelle-forming agent, and oil available under the name PROVAX® (IDEC Pharmaceuticals, San Diego, Calif.). An adjuvant can also be an immunostimulatory nucleic acid, such as a nucleic acid including a CpG motif.
In one example, the immunogenic composition is mixed with an adjuvant containing two or more of a stabilizing detergent, a micelle-forming agent, and an oil. Suitable stabilizing detergents, micelle-forming agents, and oils are detailed in U.S. Pat. Nos. 5,585,103; 5,709,860; 5,270,202; and 5,695,770, all of which are incorporated by reference herein in their entirety. A stabilizing detergent is any detergent that allows the components of the emulsion to remain as a stable emulsion. Such detergents include polysorbate 80 (TWEEN) (Sorbitan-mono-9-octadecenoate-poly(oxy-1,2-ethanediyl; manufactured by ICI Americas, Wilmington, Del.), TWEEN 40™, TWEEN 20™, TWEEN60™, ZWITTERGENT™ 3-12, TEEPOL HB7™, and SPAN85™. These detergents are usually provided in an amount of approximately 0.05 to 0.5%, such as at about 0.2%. A micelle forming agent is an agent which is able to stabilize the emulsion formed with the other components such that a micelle-like structure is formed. Such agents generally cause some irritation at the site of injection in order to recruit macrophages to enhance the cellular response. Examples of such agents include polymer surfactants described by BASF Wyandotte publications, for example, Schmolka, J. Am. Oil. Chem. Soc. 54:110, 1977, and Hunter et al., J. Immunol 129:1244, 1981, PLURONIC™ L62LF, L101, and L64, PEG1000, and TETRONIC™ 1501, 150R1, 701, 901, 1301, and 130R1. The chemical structures of such agents are well known in the art. In one embodiment, the agent is chosen to have a hydrophile-lipophile balance (HLB) of between 0 and 2, as defined by Hunter and Bennett, J. Immun. 133:3167, 1984. The agent can be provided in an effective amount, for example between 0.5 and 10%, or in an amount between 1.25 and 5%.
The oil included in the composition is chosen to promote the retention of the antigen in oil-in-water emulsion, to provide a vehicle for the desired antigen, and preferably has a melting temperature of less than 65° C. such that emulsion is formed either at room temperature (about 20° C. to 25° C.), or once the temperature of the emulsion is brought down to room temperature. Examples of such oils include squalene, Squalane, EICOSANE™, tetratetracontane, glycerol, and peanut oil or other vegetable oils. In one specific, non-limiting example, the oil is provided in an amount between 1 and 10%, or between 2.5 and 5%. The oil should be both biodegradable and biocompatible so that the body can break down the oil over time, and so that no adverse affects, such as granulomas, are evident upon use of the oil.
Immunogenic compositions can be formulated with an appropriate solid or liquid carrier, depending upon the particular mode of administration chosen. If desired, the disclosed pharmaceutical compositions can also contain minor amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, preservatives, and pH buffering agents and the like, for example sodium acetate or sorbitan monolaurate. Excipients that can be included in the disclosed compositions include flow conditioners and lubricants, for example silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol, or derivatives thereof.
Immunogenic compositions can be provided as parenteral compositions, such as for injection or infusion. Such compositions are formulated generally by mixing a disclosed therapeutic agent at the desired degree of purity, in a unit dosage injectable form (solution, suspension, or emulsion), with a pharmaceutically acceptable carrier, for example one that is non-toxic to recipients at the dosages and concentrations employed and is compatible with other ingredients of the formulation. In addition, a disclosed therapeutic agent can be suspended in an aqueous carrier, for example, in an isotonic buffer solution at a pH of about 3.0 to about 8.0, preferably at a pH of about 3.5 to about 7.4, 3.5 to 6.0, or 3.5 to about 5.0. Useful buffers include sodium citrate-citric acid and sodium phosphate-phosphoric acid, and sodium acetate/acetic acid buffers. The active ingredient, optionally together with excipients, can also be in the form of a lyophilisate and can be made into a solution prior to parenteral administration by the addition of suitable solvents. Solutions such as those that are used, for example, for parenteral administration can also be used as infusion solutions.
A form of repository or “depot” slow release preparation can be used so that therapeutically effective amounts of the preparation are delivered into the bloodstream over many hours or days following transdermal injection or delivery. Such long acting formulations can be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. The compounds can be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
Immunogenic compositions that include a disclosed therapeutic agent can be delivered by way of a pump (see Langer, supra; Sefton, CRC Crit. Ref. Biomed. Eng. 14:201, 1987; Buchwald et al., Surgery 88:507, 1980; Saudek et al., N. Engl. J. Med. 321:574, 1989) or by continuous subcutaneous infusions, for example, using a mini-pump. An intravenous bag solution can also be employed. One factor in selecting an appropriate dose is the result obtained, as measured by the methods disclosed here, as are deemed appropriate by the practitioner. Other controlled release systems are discussed in Langer (Science 249:1527-33, 1990).
In one example, a pump is implanted (for example see U.S. Pat. Nos. 6,436,091; 5,939,380; and 5,993,414). Implantable drug infusion devices are used to provide patients with a constant and long-term dosage or infusion of a therapeutic agent. Such device can be categorized as either active or passive.
Active drug or programmable infusion devices feature a pump or a metering system to deliver the agent into the patient's system. An example of such an active infusion device currently available is the Medtronic SYNCHROMED™ programmable pump. Passive infusion devices, in contrast, do not feature a pump, but rather rely upon a pressurized drug reservoir to deliver the agent of interest. An example of such a device includes the Medtronic ISOMED™.
In particular examples, immunogenic compositions including a disclosed therapeutic agent are administered by sustained-release systems. Suitable examples of sustained-release systems include suitable polymeric materials (such as, semi-permeable polymer matrices in the form of shaped articles, for example films, or microcapsules), suitable hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, and sparingly soluble derivatives (such as, for example, a sparingly soluble salt). Sustained-release compositions can be administered orally, parenterally, intracistemally, intraperitoneally, topically (as by powders, ointments, gels, drops or transdermal patch), or as an oral or nasal spray. Sustained-release matrices include polylactides (U.S. Pat. No. 3,773,919, EP 58,481), copolymers of L-glutamic acid and gamma-ethyl-L-glutamate (Sidman et al., Biopolymers 22:547-556, 1983, poly(2-hydroxyethyl methacrylate)); (Langer et al., J. Biomed. Mater. Res. 15:167-277, 1981; Langer, Chem. Tech. 12:98-105, 1982, ethylene vinyl acetate (Langer et al., Id.) or poly-D-(−)-3-hydroxybutyric acid (EP 133,988).
Polymers can be used for ion-controlled release. Various degradable and nondegradable polymeric matrices for use in controlled drug delivery are known in the art (Langer, Accounts Chem. Res. 26:537, 1993). For example, the block copolymer, polaxamer 407 exists as a viscous yet mobile liquid at low temperatures but forms a semisolid gel at body temperature. It has shown to be an effective vehicle for formulation and sustained delivery of recombinant interleukin-2 and urease (Johnston et al., Pharm. Res. 9:425, 1992; and Pec, J. Parent. Sci. Tech. 44(2):58, 1990). Alternatively, hydroxyapatite has been used as a microcarrier for controlled release of proteins (Ijntema et al., Int. J. Pharm. 112:215, 1994). In yet another aspect, liposomes are used for controlled release as well as drug targeting of the lipid-capsulated drug (Betageri et al., Liposome Drug Delivery Systems, Technomic Publishing Co., Inc., Lancaster, Pa., 1993). Numerous additional systems for controlled delivery of therapeutic proteins are known (for example, U.S. Pat. Nos. 5,055,303; 5,188,837; 4,235,871; 4,501,728;. 4,837,028; 4,957,735; and 5,019,369; 5,055,303; 5,514,670; 5,413,797; 5,268,164; 5,004,697; 4,902,505; 5,506,206; 5,271,961; 5,254,342; and 5,534,496).
Immunogenic compositions can be administered for therapeutic treatments. In therapeutic applications, a therapeutically effective amount of the immunogenic composition is administered to a subject suffering from a disease, such as HIV-1 infection or AIDS. The immunogenic composition an be administered by any means known to one of skill in the art (see Banga, A., “Parenteral Controlled Delivery of Therapeutic Peptides and Proteins,” in Therapeutic Peptides and Proteins, Technomic Publishing Co., Inc., Lancaster, Pa., 1995) such as by intramuscular, subcutaneous, or intravenous injection, but even oral, nasal, or anal administration is contemplated. To extend the time during which the peptide or protein is available to stimulate a response, the peptide or protein can be provided as an implant, an oily injection, or as a particulate system. The particulate system can be a microparticle, a microcapsule, a microsphere, a nanocapsule, or similar particle (see, for example, Banga, supra). A particulate carrier based on a synthetic polymer has been shown to act as an adjuvant to enhance the immune response, in addition to providing a controlled release. Aluminum salts can also be used as adjuvants to produce an immune response.
Immunogenic compositions can be formulated in unit dosage form, suitable for individual administration of precise dosages. In pulse doses, a bolus administration of an immunogenic composition that includes a disclosed immunogen is provided, followed by a time-period wherein no disclosed immunogen is administered to the subject, followed by a second bolus administration. A therapeutically effective amount of an immunogenic composition can be administered in a single dose, or in multiple doses, for example daily, during a course of treatment. In specific, non-limiting examples, pulse doses of an immunogenic composition that include a disclosed immunogen are administered during the course of a day, during the course of a week, or during the course of a month.
Immunogenic compositions can be administered whenever the effect (such as decreased signs, symptom, or laboratory results of HIV-1 infection) is desired. Generally, the dose is sufficient to treat or ameliorate symptoms or signs of disease without producing unacceptable toxicity to the subject. Systemic or local administration can be utilized.
Amounts effective for therapeutic use can depend on the severity of the disease and the age, weight, general state of the patient, and other clinical factors. Thus, the final determination of the appropriate treatment regimen will be made by the attending clinician. Typically, dosages used in vitro can provide useful guidance in the amounts useful for in situ administration of the pharmaceutical composition, and animal models may be used to determine effective dosages for treatment of particular disorders. Various considerations are described, for example in Gilman et al., eds., Goodman and Gilman: The Pharmacological Bases of Therapeutics, 8th ed., Pergamon Press, 1990; and Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Co., Easton, Pa., 1990. Typically, the dose range for a gp120 polypeptide is from about 0.1 μg/kg body weight to about 100 mg/kg body weight. Other suitable ranges include doses of from about 1 μg/kg to 10 mg/kg body weight. In one example, the dose is about 1.0 μg to about 50 mg, for example, 1 μg to 1 mg, such as 1 mg peptide per subject. The dosing schedule can vary from daily to as seldom as once a year, depending on clinical factors, such as the subject's sensitivity to the peptide and tempo of their disease. Therefore, a subject can receive a first dose of a disclosed therapeutic molecule, and then receive a second dose (or even more doses) at some later time(s), such as at least one day later, such as at least one week later.
The pharmaceutical compositions disclosed herein can be prepared and administered in dose units. Solid dose units include tablets, capsules, transdermal delivery systems, and suppositories. The administration of a therapeutic amount can be carried out both by single administration in the form of an individual dose unit or else several smaller dose units and also by multiple administrations of subdivided doses at specific intervals. Suitable single or divided doses include, but are not limited to about 0.01, 0.1, 0.5, 1, 3, 5, 10, 15, 30, or 50 μg protein/kg/day
The nucleic acid constructs encoding antigenic gp120 polypeptides described herein are used, for example, in combination, as pharmaceutical compositions (medicaments) for use in therapeutic, for example, prophylactic regimens (such as vaccines) and administered to subjects (for example, primate subjects such as human subjects) to elicit an immune response against one or more clade or strain of HIV. For example, the compositions described herein can be administered to a human (or non-human) subject prior to infection with HIV to inhibit infection by or replication of the virus. Thus, the pharmaceutical compositions described above can be administered to a subject to elicit a protective immune response against HIV. To elicit an immune response, a therapeutically effective (for example, immunologically effective) amount of the nucleic acid constructs are administered to a subject, such as a human (or non-human) subject.
Immunization by nucleic acid constructs is well known in the art and taught, for example, in U.S. Pat. No. 5,643,578 (which describes methods of immunizing vertebrates by introducing DNA encoding a desired antigen to elicit a cell-mediated or a humoral response), and U.S. Pat. Nos. 5,593,972 and 5,817,637 (which describe operably linking a nucleic acid sequence encoding an antigen to regulatory sequences enabling expression). U.S. Pat. No. 5,880,103 describes several methods of delivery of nucleic acids encoding immunogenic peptides or other antigens to an organism. The methods include liposomal delivery of the nucleic acids (or of the synthetic peptides themselves), and immune-stimulating constructs, or ISCOMS™, negatively charged cage-like structures of 30-40 nm in size formed spontaneously on mixing cholesterol and QUIL A™ (saponin).
For administration of gp120 nucleic acid molecules, the nucleic acid can be delivered intracellularly, for example by expression from an appropriate nucleic acid expression vector which is administered so that it becomes intracellular, such as by use of a retroviral vector (see U.S. Pat. No. 4,980,286), or by direct injection, or by use of microparticle bombardment (such as a gene gun; Biolistic, Dupont), or coating with lipids or cell-surface receptors or transfecting agents, or by administering it in linkage to a homeobox-like peptide which is known to enter the nucleus (for example Joliot et al., Proc. Natl. Acad. Sci. USA 1991, 88:1864-8) The present disclosure includes all forms of nucleic acid delivery, including synthetic oligos, naked DNA, plasmid and viral, integrated into the genome or not.
In another approach to using nucleic acids for immunization, an immunogenic gp120 polypeptide can also be expressed by attenuated viral hosts or vectors or bacterial vectors. Recombinant vaccinia virus, adeno-associated virus (AAV), herpes virus, retrovirus, or other viral vectors can be used to express the peptide or protein, thereby eliciting a CTL response. For example, vaccinia vectors and methods useful in immunization protocols are described in U.S. Pat. No. 4,722,848. BCG (Bacillus Calmette Guerin) provides another vector for expression of the peptides (see Stover, Nature 351:456-460, 1991).
In one example, a viral vector is utilized. These vectors include, but are not limited to, adenovirus, herpes virus, vaccinia, or an RNA virus such as a retrovirus. In one example, the retroviral vector is a derivative of a murine or avian retrovirus. Examples of retroviral vectors in which a single foreign gene can be inserted include, but are not limited to: Moloney murine leukemia virus (MoMuLV), Harvey murine sarcoma virus (HaMuSV), murine mammary tumor virus (MuMTV), and Rous Sarcoma Virus (RSV). When the subject is a human, a vector such as the gibbon ape leukemia virus (GaLV) can be utilized. A number of additional retroviral vectors can incorporate multiple genes. All of these vectors can transfer or incorporate a gene for a selectable marker so that transduced cells can be identified and generated. By inserting a nucleic acid sequence encoding a gp120 polypeptide into the viral vector, along with another gene that encodes the ligand for a receptor on a specific target cell, for example, the vector is now target specific. Retroviral vectors can be made target specific by attaching, for example, a sugar, a glycolipid, or a protein. Preferred targeting is accomplished by using an antibody to target the retroviral vector. Those of skill in the art will know of, or can readily ascertain without undue experimentation, specific polynucleotide sequences which can be inserted into the retroviral genome or attached to a viral envelope to allow target specific delivery of the retroviral vector containing the polynucleotide encoding a gp120 polypeptide.
Since recombinant retroviruses are defective, they need assistance in order to produce infectious vector particles. This assistance can be provided, for example, by using helper cell lines that contain plasmids encoding all of the structural genes of the retrovirus under the control of regulatory sequences within the LTR. These plasmids are missing a nucleotide sequence that enables the packaging mechanism to recognize an RNA transcript for encapsidation. Helper cell lines that have deletions of the packaging signal include, but are not limited to Q2, PA317, and PA12, for example. These cell lines produce empty virions, since no genome is packaged. If a retroviral vector is introduced into such cells in which the packaging signal is intact, but the structural genes are replaced by other genes of interest, the vector can be packaged and vector virion produced.
Suitable formulations for the nucleic acid constructs, include aqueous and non-aqueous solutions, isotonic sterile solutions, which can contain anti-oxidants, buffers, and bacteriostats, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives. The formulations can be presented in unit-dose or multi-dose sealed containers, such as ampules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, water, immediately prior to use. Extemporaneous solutions and suspensions can be prepared from sterile powders, granules, and tablets. Preferably, the carrier is a buffered saline solution. More preferably, the composition for use in the inventive method is formulated to protect the nucleic acid constructs from damage prior to administration. For example, the composition can be formulated to reduce loss of the adenoviral vectors on devices used to prepare, store, or administer the expression vector, such as glassware, syringes, or needles. The compositions can be formulated to decrease the light sensitivity and/or temperature sensitivity of the components. To this end, the composition preferably comprises a pharmaceutically acceptable liquid carrier, such as, for example, those described above, and a stabilizing agent selected from the group consisting of polysorbate 80, L-arginine, polyvinylpyrrolidone, trehalose, and combinations thereof.
In therapeutic applications, a therapeutically effective amount of the composition is administered to a subject prior to or following exposure to or infection by HIV. When administered prior to exposure, the therapeutic application can be referred to as a prophylactic administration (such as in the form of a vaccine). Single or multiple administrations of the compositions are administered depending on the dosage and frequency as required and tolerated by the subject. In one embodiment, the dosage is administered once as a bolus, but in another embodiment can be applied periodically until a therapeutic result, such as a protective immune response, is achieved. Generally, the dose is sufficient to treat or ameliorate symptoms or signs of disease without producing unacceptable toxicity to the subject. Systemic or local administration can be utilized.
In the context of nucleic acid vaccines, naturally occurring or synthetic immunostimulatory compositions that bind to and stimulate receptors involved in innate immunity can be administered along with nucleic acid constructs encoding the gp120 polypeptides. For example, agents that stimulate certain Toll-like receptors (such as TLR7, TLR8 and TLR9) can be administered in combination with the nucleic acid constructs encoding gp120 polypeptides. In some embodiments, the nucleic acid construct is administered in combination with immunostimulatory CpG oligonucleotides.
Nucleic acid constructs encoding gp120 polypeptides can be introduced in vivo as naked DNA plasmids. DNA vectors can be introduced into the desired host cells by methods known in the art, including but not limited to transfection, electroporation (for example, transcutaneous electroporation), microinjection, transduction, cell fusion, DEAE dextran, calcium phosphate precipitation, use of a gene gun, or use of a DNA vector transporter (See for example, Wu et al. J. Biol. Chem., 267:963-967, 1992; Wu and Wu J. Biol. Chem., 263:14621-14624, 1988; and Williams et al. Proc. Natl. Acad. Sci. USA 88:2726-2730, 1991). As described in detail in the Examples, a needleless delivery device, such as a BIOJECTOR® needleless injection device can be utilized to introduce the therapeutic nucleic acid constructs in vivo. Receptor-mediated DNA delivery approaches can also be used (Curiel et al. Hum. Gene Ther., 3:147-154, 1992; and Wu and Wu, J. Biol. Chem., 262:4429-4432, 1987). Methods for formulating and administering naked DNA to mammalian muscle tissue are disclosed in U.S. Pat. Nos. 5,580,859 and 5,589,466, both of which are herein incorporated by reference. Other molecules are also useful for facilitating transfection of a nucleic acid in vivo, such as a cationic oligopeptide (for example, WO95/21931), peptides derived from DNA binding proteins (for example, WO96/25508), or a cationic polymer (for example, WO95/21931).
Another well known method that can be used to introduce nucleic acid constructs encoding gp120 immunogens into host cells is particle bombardment (also know as biolistic transformation). Biolistic transformation is commonly accomplished in one of several ways. One common method involves propelling inert or biologically active particles at cells. This technique is disclosed in, for example, U.S. Pat. Nos. 4,945,050, 5,036,006; and 5,100,792, all to Sanford et al., which are hereby incorporated by reference. Generally, this procedure involves propelling inert or biologically active particles at the cells under conditions effective to penetrate the outer surface of the cell and to be incorporated within the interior thereof. When inert particles are utilized, the plasmid can be introduced into the cell by coating the particles with the plasmid containing the exogenous DNA. Alternatively, the target cell can be surrounded by the plasmid so that the plasmid is carried into the cell by the wake of the particle.
Alternatively, the vector can be introduced in vivo by lipofection. For the past decade, there has been increasing use of liposomes for encapsulation and transfection of nucleic acids in vitro. Synthetic cationic lipids designed to limit the difficulties and dangers encountered with liposome mediated transfection can be used to prepare liposomes for in vivo transfection of a gene encoding a marker (Felgner et. al. Proc. Natl. Acad. Sci. USA 84:7413-7417, 1987; Mackey, et al. Proc. Natl. Acad. Sci. USA 85:8027-8031, 1988; Ulmer et al. Science 259:1745-1748, 1993). The use of cationic lipids can promote encapsulation of negatively charged nucleic acids, and also promote fusion with negatively charged cell membranes (Felgner and Ringold Science 337:387-388, 1989). Particularly useful lipid compounds and compositions for transfer of nucleic acids are described in WO95/18863 and WO96/17823, and in U.S. Pat. No. 5,459,127, herein incorporated by reference.
As with the immunogenic polypeptide, the nucleic acid compositions may be administered in a single dose, or multiple doses separated by a time interval can be administered to elicit an immune response against HIV. For example, two doses, or three doses, or four doses, or five doses, or six doses or more can be administered to a subject over a period of several weeks, several months or even several years, to optimize the immune response.
It may be advantageous to administer the immunogenic compositions disclosed herein with other agents such as proteins, peptides, antibodies, and other anti-HIV agents. Examples of such anti-HIV therapeutic agents include nucleoside reverse transcriptase inhibitors, such as abacavir, AZT, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine, zidovudine, and the like, non-nucleoside reverse transcriptase inhibitors, such as delavirdine, efavirenz, nevirapine, protease inhibitors such as amprenavir, atazanavir, indinavir, lopinavir, nelfinavir osamprenavir, ritonavir, saquinavir, tipranavir, and the like, and fusion protein inhibitors such as enfuvirtide and the like. In certain embodiments, immunonogenic compositions are administered concurrently with other anti-HIV therapeutic agents. In certain embodiments, the immunonogenic compositions are administered sequentially with other anti-HIV therapeutic agents, such as before or after the other agent. One of ordinary skill in the art would know that sequential administration can mean immediately following or after an appropriate period of time, such as hours days, weeks, months, or even years later.
While not being bound by theory, it is believed that CD4 binding to gp120 triggers the exposure of the immunodominant V3 loop. Thus, co-administration of soluble forms of CD4, such as the fragments described herein, or an antibody that binds to the CD4 binding site, can lead to enhanced elicitation of an immunogenic response to gp120.
In certain embodiments, immunonogenic compositions disclosed herein are administered with a soluble portion of CD4, for example a sufficient portion of the CD4 to bind to the CD4 binding site on gp120. Such soluble fragments typically include both the D1 and D2 extracellular domains of CD4 (D1D2) or sCD4 (which is comprised of D1 D2 D3 and D4 domains of CD4), although smaller fragments may also provide specific and functional CD4-like binding. In certain embodiments, the gp120 polypeptide with an extended V3 loop or a nucleic acid encoding the same is administered concurrently with a soluble portion of CD4. In other embodiments, the gp120 polypeptide with an extended V3 loop or a nucleic acid encoding the same is administered concurrently with an antibody that binds to the CD4 binding site on gp120.
The immunogenic gp120 polypeptides and nucleic acid encoding these polypeptides (such as stabilized gp120 polypeptides, gp120 polypeptides with an extended V3 loop) can be used in a novel multistep immunization regime. Typically, this regime includes administering to a subject a therapeutically effective amount of a gp120 polypeptide as disclosed herein (the prime) and boosting the immunogenic response with stabilized gp140 trimer (Yang et al. J. Virol. 76(9):4634-42, 2002) after an appropriate period of time. The method of eliciting such an immune reaction is what is known as “prime-boost.” In this method, a gp120 polypeptide is initially administered to a subject and at periodic times thereafter stabilized gp140 trimer boosts are administered. Examples of stabilized gp140 or gp120 trimers can be found for example in U.S. Pat. No. 6,911,205 which is incorporated herein in its entirely.
The prime can be administered as a single dose or multiple doses, for example two doses, three doses, four doses, five doses, six doses or more can be administered to a subject over day week or months. The boost can be administered as a single dose or multiple doses, for example two to six doses, or more can be administered to a subject over a day, a week or months. Multiple boosts can also be given, such one to five, or more.
The boosts can be an identical molecule or a somewhat different, but related, molecule. For example, one preferred strategy with the gp120 polypeptides of the present disclosure would be to prime using a stabilized gp120 polypeptide or a gp120 polypeptide with an extended V3 and boosting periodically with stabilized trimers where the gp120 units are designed to come closer and closer to the wild type gp120 over the succession of boosts. For example, the first prime could be a stabilized gp120 polypeptide, with a boost by a stabilized trimer form with the same stabilized gp120 or a trimer with less deletions or changes from the native gp120 conformation, with subsequent boosts using trimers that had still less deletions or changes from the native gp120 conformation until the boosts were finally being given by trimers with a gp120 portion based on the native wild type HIV gp120.
One can also use cocktails containing a variety of different HIV strains to prime and boost with trimers from a variety of different HIV strains or with trimers that are a mixture of multiple HIV strains. For example, the first prime could be with a gp120 polypeptide from one primary HIV isolate, with subsequent boosts using trimers from different primary isolates.
In certain embodiments, the prime is a nucleic acid construct comprising a nucleic acid sequence encoding a gp120 immunogen as disclosed herein, for example an nucleotide sequence encoding the amino acid sequence set forth as SEQ ID NO: 1 or SEQ ID NO: 2, or the nucleotide sequence as set forth as on of SEQ ID NO: 4-18 or a degenerate variant thereof. In certain embodiments the boost comprises a nucleic acid sequence encoding a stabilized gp140 trimer.
V. Crystal Structures
The stabilized gp120 polypeptides and the gp120 polypeptides with an extended V3 loop disclosed herein can be used to produce detailed models of gp120 polypeptide atomic structure. Exemplary coordinate data is given in Table 1 and Table 2. The atomic coordinate data is disclosed herein, or the coordinate data derived from homologous proteins may be used to build a three-dimensional model of a gp120 polypeptide or a portion thereof, for example by providing a sufficient number of atoms of the stabilized form of gp120 or the gp120 with the V3 loop in the extended conformation as defined by the coordinates of Table 1 or Table 2 which represent a surface or three-dimensional region of interest, such as an antigenic surface or ligand binding site. Thus, there can be provided the coordinates of at least about 5, such at least about 10, at least about 20, at least about 30, at least at least about 40, at least about 50, at least about 60, at least about 70, at least about 80, at least about 90, at least about 100, at least about 150, at least about 200, at least about 250, at least about 300, at least about 350, at least about 400, at least about 450, at least about 500 or more atoms of the structure, such as defined by the coordinates of Table 1 or Table 2. Thus, a sub-domain, region, or fragment of interest of the stabilized form of gp120 or the gp120 with the extended V3 loop which is in the vicinity of the antigenic surface, can be provided for identifying or rationally designing a compound or drug, such as an immunogen. A “sub-domain,” “region,” or “fragment” can mean at least one, for example, one, two, three, four, or more, element(s) of secondary structure of particular regions of the stabilized form of gp120 or the gp120 with the extended V3 loop gp120 with the extended V3 loop, and includes those set forth in Table 1 and Table 2.
Any available computational methods may be used to build the three dimensional model. As a starting point, the X-ray diffraction pattern obtained from the assemblage of the molecules or atoms in a crystalline version of a gp120 polypeptide can be used to build an electron density map using tools well known to those skilled in the art of crystallography and X-ray diffraction techniques. Additional phase information extracted either from the diffraction data and available in the published literature and/or from supplementing experiments may then used to complete the reconstruction.
For an overview of the procedures of collecting, analyzing, and utilizing X-ray diffraction data for the construction of electron densities see, for example, Campbell et al., Biological Spectioscopy, The Benjamin/Cummings Publishing Co., Inc., Menlo Park, Calif., 1984; Cantor et al., Biophysical Chemistry, Part II: Techniques for the study of biological structure and function, W.H. Freeman and Co., San Francisco, Calif. 1980; A. T. Brunger, X-plor Version 3.1: A system for X-ray crystallography and NMR, Yale Univ. Pr., New Haven, Conn. 1993; M. M. Woolfson, An Introduction to X-ray Crystallography, Cambridge Univ. Pr., Cambridge, UK, 1997; J. Drenth, Principles of Protein X-ray Crystallography (Springer Advanced Texts in Chemistry), Springer Verlag; Berlin, 1999; Tsirelson et al, Electron Density and Bonding in Crystals: Principles, Theory and X-ray Diffraction Experiments in Solid State Physics and Chemistry, Inst. of Physics Pub., 1996; each of which is herein specifically incorporated by reference in their entirety.
Information on molecular modeling can be found for example in, M. Schlecht, Molecular Modeling on the PC, 1998, John Wiley & Sons; Gans et al., Fundamental Principals of Molecular Modeling, Plenum Pub. Corp., 1996; N. C. Cohen (editor), Guidebook on Molecular Modeling in Drug Design, Academic Press, 1996; and W. B. Smith, Introduction to Theoretical Organic Chemistry and Molecular Modeling, 1996.
Typically, a well-ordered crystal that will diffract x-rays strongly is used to solve the three-dimensional structure of a protein by x-ray crystallography. The crystallographic method directs a beam of x-rays onto a regular, repeating array of many identical molecules. The x-rays are diffracted from it in a pattern from which the atomic positions of the atom that make up the molecule of interest can be determined.
Substantially pure and homogeneous protein samples are usually used for crystallization. Typically, crystals form when molecules are precipitated very slowly from supersaturated solutions. A typical procedure for making protein crystals is the hanging-drop method, in which a drop of protein solution is brought very gradually to supersaturation by loss of water from the droplet to the larger reservoir that contains salt, polyethylene glycol, or other solution that functions as a hydroattractant, although any other method that generates diffraction quality crystals can be used. In some examples diffraction quality crystals are obtained by seeding the supersaturated solution with smaller crystals that serve as templates.
Powerful x-ray beams can be produced from synchrotron storage rings where electrons (or positrons) travel close to the speed of light. These particles emit very strong radiation at all wavelengths from short gamma rays to visible light. When used as an x-ray source, only radiation within a window of suitable wavelengths is channeled from the storage ring.
In diffraction experiments a narrow and parallel beam of x-rays is taken out from the x-ray source and directed onto the crystal to produce diffracted beams. The incident x-ray beam causes damage to both protein and solvent molecules. The crystal is, therefore, usually cooled to prolong its lifetime (for example to −220° to −50° C.). In some examples, single crystals are used to obtain a data set, while in other examples, multiple crystals are used to obtain a data set. The x-ray beam must strike the crystal from many different directions to produce all possible diffraction spots, thereby creating a complete data set. Therefore, the crystal is rotated relative to the beam during data collection. The diffracted spots are recorded either on a film, or by an electronic detector, both of which are commercially available.
When the primary beam from an x-ray source strikes the crystal, x-rays interact with the electrons on each atom in the crystal and cause them to oscillate. The oscillating electrons serve as a new source of x-rays, which are emitted in almost all directions in a process referred to as scattering. When atoms (and hence their electrons) are arranged in a regular three-dimensional array, as in a crystal, the x-rays emitted from the oscillating electrons interfere with one another. In most cases, these x-rays, colliding from different directions, cancel each other out; those from certain directions, however, will add together to produce diffracted beams of radiation that can be recorded as a pattern on a photographic plate or detector.
The diffraction pattern obtained in an x-ray experiment is related to the crystal that caused the diffraction. X-rays that are reflected from adjacent planes travel different distances, and diffraction only occurs when the difference in distance is equal to the wavelength of the x-ray beam. This distance is dependent on the reflection angle, which is equal to the angle between the primary beam and the planes.
Each atom in a crystal scatters x-rays in all directions, and only those that positively interfere with one another, according to Bragg's law (2d sin θ=λ), give rise to diffracted beams that can be recorded as a distinct diffraction spot above background. Each diffraction spot is the result of interference of all x-rays with the same diffraction angle emerging from all atoms. To extract information about individual atoms from such a system requires considerable computation. The mathematical tool that is used to handle such problems is called the Fourier transform.
Each diffracted beam, which is recorded as a spot on the film, is defined by three properties: the amplitude, which is measured as the intensity of the spot; the wavelength, which is determined by the x-ray source; and the phase information, which is lost in x-ray experiments and must be calculated. All three properties are used for all of the diffracted beams, in order to determine the position of the atoms giving rise to the diffracted beams. Methods of determining the phases are well know in the art.
For example, phase differences between diffracted spots can be determined from intensity changes following heavy atom derivatization. Another example would be determining the phases by molecular replacement.
The amplitudes and the phases of the diffraction data from the protein crystals are used to calculate an electron-density map of the repeating unit of the crystal. A model of the particular amino acid sequence is built to approximate the electron density map.
The initial model will contain some errors. Provided the protein crystals diffract to high enough resolution (e.g., better than 3.5 Å), most or substantially all of the errors can be removed by crystallographic refinement of the model using computer algorithms. In this process, the model is changed to minimize the difference between the experimentally observed diffraction amplitudes and those calculated for a hypothetical crystal containing the model. This difference is expressed as an R factor (residual disagreement) which is 0.0 for exact agreement and about 0.59 for total disagreement.
Typically, the R factor of a refined model is preferably between 0.15 and 0.35 (such as less than about 0.24-0.28) for a well-determined protein structure. The residual difference is a consequence of errors and imperfections in the data. These derive from various sources, including slight variations in the conformation of the protein molecules, as well as inaccurate corrections both for the presence of solvent and for differences in the orientation of the microcrystals from which the crystal is built. Thus, the final model represents an average of molecules that are slightly different in both conformation and orientation.
In refined structures at high resolution, there are usually no major errors in the orientation of individual residues, and the estimated errors in atomic positions are usually around 0.1-0.2 Å, provided the amino acid sequence is known.
Most x-ray structures are determined to a resolution between 1.7 Å. and 3.5 Å. Electron-density maps with this resolution range are preferably interpreted by fitting the known amino acid sequences into regions of electron density in which individual atoms are not resolved.
VI. Crystals Structure of Stabilized gp120
The present disclosure also relates to the crystals obtained from stabilized forms of gp120, the crystal structures of the stabilized forms of gp120, the three-dimensional coordinates of the stabilized forms of gp120 polypeptide and three-dimensional structures of models of stabilized forms of gp120. Table 1 provides the atomic coordinates of the crystal structure of the polypeptide encoded by SEQ ID NO: 14.
TABLE 1
The structural coordinates of an exemplary stabilized form of gp120 at atomic
resolution
ATOM
1
CB
GLU
83
18.617
−44.257
86.334
1.00
108.57
ATOM
2
CG
GLU
83
17.192
−44.735
86.515
1.00
108.41
ATOM
3
CD
GLU
83
16.205
−43.880
85.755
1.00
108.12
ATOM
4
OE1
GLU
83
16.358
−43.762
84.524
1.00
108.57
ATOM
5
OE2
GLU
83
15.280
−43.327
86.385
1.00
107.50
ATOM
6
C
GLU
83
19.772
−46.457
86.717
1.00
109.62
ATOM
7
O
GLU
83
18.985
−47.321
87.117
1.00
110.00
ATOM
8
N
GLU
83
20.954
−44.298
87.129
1.00
108.79
ATOM
9
CA
GLU
83
19.642
−45.003
87.189
1.00
109.16
ATOM
10
N
VAL
84
20.768
−46.714
85.869
1.00
109.52
ATOM
11
CA
VAL
84
21.044
−48.053
85.341
1.00
109.11
ATOM
12
CB
VAL
84
20.172
−48.376
84.093
1.00
108.87
ATOM
13
CG1
VAL
84
18.713
−48.542
84.498
1.00
108.27
ATOM
14
CG2
VAL
84
20.302
−47.271
83.061
1.00
109.39
ATOM
15
C
VAL
84
22.526
−48.185
84.964
1.00
108.77
ATOM
16
O
VAL
84
22.925
−47.846
83.851
1.00
108.35
ATOM
17
N
VAL
85
23.332
−48.684
85.900
1.00
108.71
ATOM
18
CA
VAL
85
24.774
−48.848
85.689
1.00
108.45
ATOM
19
CB
VAL
85
25.515
−49.032
87.038
1.00
108.05
ATOM
20
CG1
VAL
85
25.521
−47.724
87.807
1.00
108.41
ATOM
21
CG2
VAL
85
24.837
−50.110
87.862
1.00
107.81
ATOM
22
C
VAL
85
25.175
−49.994
84.754
1.00
108.29
ATOM
23
O
VAL
85
24.757
−51.138
84.941
1.00
108.64
ATOM
24
N
LEU
86
25.997
−49.670
83.755
1.00
107.51
ATOM
25
CA
LEU
86
26.483
−50.644
82.774
1.00
106.03
ATOM
26
CB
LEU
86
26.839
−49.943
81.458
1.00
104.36
ATOM
27
CG
LEU
86
25.737
−49.391
80.552
1.00
103.07
ATOM
28
CD1
LEU
86
24.750
−48.544
81.333
1.00
102.61
ATOM
29
CD2
LEU
86
26.390
−48.575
79.450
1.00
101.71
ATOM
30
C
LEU
86
27.720
−51.369
83.298
1.00
105.81
ATOM
31
O
LEU
86
28.354
−50.916
84.254
1.00
105.88
ATOM
32
N
VAL
87
28.065
−52.490
82.668
1.00
105.43
ATOM
33
CA
VAL
87
29.231
−53.263
83.083
1.00
104.73
ATOM
34
CB
VAL
87
28.827
−54.553
83.805
1.00
104.68
ATOM
35
CG1
VAL
87
28.000
−54.214
85.032
1.00
104.54
ATOM
36
CG2
VAL
87
28.057
−55.462
82.857
1.00
105.03
ATOM
37
C
VAL
87
30.119
−53.643
81.910
1.00
104.29
ATOM
38
O
VAL
87
29.635
−53.933
80.813
1.00
103.86
ATOM
39
N
ASN
88
31.425
−53.652
82.166
1.00
104.01
ATOM
40
CA
ASN
88
32.428
−53.982
81.155
1.00
103.78
ATOM
41
CB
ASN
88
32.360
−55.474
80.781
1.00
104.65
ATOM
42
CG
ASN
88
32.859
−56.393
81.902
1.00
105.20
ATOM
43
OD1
ASN
88
33.953
−56.199
82.445
1.00
104.86
ATOM
44
ND2
ASN
88
32.056
−57.399
82.235
1.00
104.99
ATOM
45
C
ASN
88
32.252
−53.117
79.909
1.00
102.44
ATOM
46
O
ASN
88
32.505
−53.561
78.787
1.00
101.94
ATOM
47
N
VAL
89
31.822
−51.875
80.122
1.00
100.88
ATOM
48
CA
VAL
89
31.614
−50.931
79.032
1.00
98.81
ATOM
49
CB
VAL
89
30.231
−50.258
79.127
1.00
98.28
ATOM
50
CG1
VAL
89
30.035
−49.322
77.953
1.00
97.33
ATOM
51
CG2
VAL
89
29.139
−51.310
79.151
1.00
98.08
ATOM
52
C
VAL
89
32.679
−49.841
79.051
1.00
97.94
ATOM
53
O
VAL
89
33.180
−49.461
80.113
1.00
97.43
ATOM
54
N
THR
90
33.020
−49.348
77.864
1.00
96.73
ATOM
55
CA
THR
90
34.020
−48.295
77.724
1.00
95.18
ATOM
56
CB
THR
90
35.403
−48.891
77.319
1.00
95.36
ATOM
57
OG1
THR
90
36.380
−47.845
77.263
1.00
95.05
ATOM
58
CG2
THR
90
35.324
−49.591
75.962
1.00
95.57
ATOM
59
C
THR
90
33.551
−47.260
76.686
1.00
93.85
ATOM
60
O
THR
90
33.505
−47.539
75.481
1.00
93.47
ATOM
61
N
GLU
91
33.196
−46.069
77.177
1.00
91.35
ATOM
62
CA
GLU
91
32.707
−44.963
76.347
1.00
87.86
ATOM
63
CB
GLU
91
31.343
−44.504
76.865
1.00
88.15
ATOM
64
CG
GLU
91
30.189
−44.701
75.899
1.00
89.11
ATOM
65
CD
GLU
91
30.231
−43.732
74.737
1.00
90.17
ATOM
66
OE1
GLU
91
29.248
−43.679
73.968
1.00
90.39
ATOM
67
OE2
GLU
91
31.249
−43.023
74.591
1.00
90.88
ATOM
68
C
GLU
91
33.676
−43.781
76.358
1.00
85.11
ATOM
69
O
GLU
91
34.317
−43.509
77.369
1.00
85.37
ATOM
70
N
ASN
92
33.783
−43.076
75.235
1.00
81.78
ATOM
71
CA
ASN
92
34.683
−41.928
75.151
1.00
78.41
ATOM
72
CB
ASN
92
35.342
−41.832
73.778
1.00
79.10
ATOM
73
CG
ASN
92
36.358
−42.903
73.549
1.00
79.88
ATOM
74
OD1
ASN
92
36.973
−43.404
74.492
1.00
80.64
ATOM
75
ND2
ASN
92
36.568
−43.252
72.285
1.00
80.59
ATOM
76
C
ASN
92
34.001
−40.602
75.405
1.00
75.77
ATOM
77
O
ASN
92
33.114
−40.198
74.650
1.00
75.80
ATOM
78
N
PHE
93
34.426
−39.915
76.455
1.00
71.82
ATOM
79
CA
PHE
93
33.870
−38.608
76.751
1.00
68.48
ATOM
80
CB
PHE
93
33.622
−38.429
78.244
1.00
67.44
ATOM
81
CG
PHE
93
32.495
−39.245
78.781
1.00
67.39
ATOM
82
CD1
PHE
93
32.554
−40.629
78.775
1.00
68.23
ATOM
83
CD2
PHE
93
31.396
−38.629
79.358
1.00
68.44
ATOM
84
CE1
PHE
93
31.537
−41.393
79.346
1.00
68.02
ATOM
85
CE2
PHE
93
30.373
−39.382
79.931
1.00
69.14
ATOM
86
CZ
PHE
93
30.446
−40.768
79.926
1.00
68.02
ATOM
87
C
PHE
93
34.888
−37.568
76.319
1.00
66.64
ATOM
88
O
PHE
93
36.094
−37.801
76.418
1.00
66.70
ATOM
89
N
ASN
94
34.405
−36.436
75.821
1.00
63.67
ATOM
90
CA
ASN
94
35.277
−35.344
75.439
1.00
61.19
ATOM
91
CB
ASN
94
35.618
−35.387
73.950
1.00
61.27
ATOM
92
CG
ASN
94
36.609
−34.300
73.550
1.00
61.92
ATOM
93
OD1
ASN
94
37.602
−34.062
74.241
1.00
61.52
ATOM
94
ND2
ASN
94
36.351
−33.647
72.422
1.00
61.78
ATOM
95
C
ASN
94
34.442
−34.119
75.767
1.00
59.74
ATOM
96
O
ASN
94
33.882
−33.482
74.893
1.00
60.53
ATOM
97
N
TRP
95
34.345
−33.831
77.055
1.00
57.77
ATOM
98
CA
TRP
95
33.579
−32.719
77.567
1.00
55.79
ATOM
99
CB
TRP
95
33.948
−32.471
79.030
1.00
53.78
ATOM
100
CG
TRP
95
35.277
−31.803
79.223
1.00
49.89
ATOM
101
CD2
TRP
95
35.534
−30.615
79.971
1.00
50.17
ATOM
102
CE2
TRP
95
36.913
−30.357
79.903
1.00
49.60
ATOM
103
CE3
TRP
95
34.727
−29.734
80.707
1.00
50.04
ATOM
104
CD1
TRP
95
36.474
−32.211
78.737
1.00
49.33
ATOM
105
NE1
TRP
95
37.468
−31.354
79.134
1.00
49.08
ATOM
106
CZ2
TRP
95
37.513
−29.263
80.533
1.00
49.33
ATOM
107
CZ3
TRP
95
35.316
−28.650
81.335
1.00
49.36
ATOM
108
CH2
TRP
95
36.696
−28.424
81.246
1.00
50.29
ATOM
109
C
TRP
95
33.733
−31.432
76.782
1.00
55.51
ATOM
110
O
TRP
95
32.832
−30.588
76.793
1.00
55.05
ATOM
111
N
CYS
96
34.876
−31.286
76.114
1.00
55.79
ATOM
112
CA
CYS
96
35.183
−30.109
75.309
1.00
56.39
ATOM
113
C
CYS
96
34.565
−30.210
73.922
1.00
55.35
ATOM
114
O
CYS
96
35.144
−29.765
72.935
1.00
55.34
ATOM
115
CB
CYS
96
36.705
−29.935
75.183
1.00
59.56
ATOM
116
SG
CYS
96
37.516
−29.511
76.772
1.00
65.71
ATOM
117
N
LYS
97
33.370
−30.781
73.863
1.00
54.38
ATOM
118
CA
LYS
97
32.641
−30.968
72.619
1.00
53.06
ATOM
119
CB
LYS
97
33.439
−31.832
71.655
1.00
54.39
ATOM
120
CG
LYS
97
34.407
−31.101
70.750
1.00
57.02
ATOM
121
CD
LYS
97
35.090
−32.103
69.834
1.00
59.38
ATOM
122
CE
LYS
97
36.181
−31.488
68.980
1.00
60.34
ATOM
123
NZ
LYS
97
36.872
−32.554
68.187
1.00
60.06
ATOM
124
C
LYS
97
31.366
−31.691
72.967
1.00
52.61
ATOM
125
O
LYS
97
31.042
−32.698
72.363
1.00
53.46
ATOM
126
N
ASN
98
30.653
−31.195
73.965
1.00
52.56
ATOM
127
CA
ASN
98
29.410
−31.833
74.362
1.00
52.14
ATOM
128
CB
ASN
98
29.300
−31.911
75.889
1.00
50.77
ATOM
129
CG
ASN
98
28.087
−32.706
76.342
1.00
49.63
ATOM
130
OD1
ASN
98
26.961
−32.405
75.957
1.00
48.41
ATOM
131
ND2
ASN
98
28.314
−33.723
77.168
1.00
48.49
ATOM
132
C
ASN
98
28.232
−31.056
73.788
1.00
52.73
ATOM
133
O
ASN
98
28.181
−29.825
73.873
1.00
52.21
ATOM
134
N
ASP
99
27.286
−31.780
73.202
1.00
53.95
ATOM
135
CA
ASP
99
26.107
−31.160
72.601
1.00
55.38
ATOM
136
CB
ASP
99
25.354
−32.184
71.745
1.00
58.50
ATOM
137
CG
ASP
99
25.615
−32.009
70.253
1.00
60.48
ATOM
138
OD1
ASP
99
25.206
−32.892
69.462
1.00
61.59
ATOM
139
OD2
ASP
99
26.222
−30.982
69.877
1.00
61.09
ATOM
140
C
ASP
99
25.142
−30.546
73.608
1.00
54.26
ATOM
141
O
ASP
99
24.342
−29.676
73.260
1.00
54.68
ATOM
142
N
MET
100
25.208
−31.008
74.851
1.00
51.85
ATOM
143
CA
MET
100
24.331
−30.496
75.889
1.00
49.13
ATOM
144
CB
MET
100
24.357
−31.424
77.094
1.00
48.72
ATOM
145
CG
MET
100
24.159
−32.873
76.743
1.00
49.12
ATOM
146
SD
MET
100
24.699
−33.947
78.077
1.00
48.08
ATOM
147
CE
MET
100
23.233
−33.971
79.064
1.00
49.17
ATOM
148
C
MET
100
24.783
−29.110
76.308
1.00
47.86
ATOM
149
O
MET
100
23.969
−28.274
76.678
1.00
48.48
ATOM
150
N
VAL
101
26.085
−28.867
76.253
1.00
46.25
ATOM
151
CA
VAL
101
26.616
−27.569
76.641
1.00
45.39
ATOM
152
CB
VAL
101
28.145
−27.522
76.472
1.00
45.11
ATOM
153
CG1
VAL
101
28.654
−26.126
76.755
1.00
44.71
ATOM
154
CG2
VAL
101
28.801
−28.517
77.401
1.00
43.94
ATOM
155
C
VAL
101
25.994
−26.455
75.800
1.00
45.33
ATOM
156
O
VAL
101
25.579
−25.426
76.318
1.00
45.54
ATOM
157
N
GLU
102
25.918
−26.676
74.498
1.00
45.19
ATOM
158
CA
GLU
102
25.371
−25.685
73.599
1.00
46.23
ATOM
159
CB
GLU
102
25.770
−26.016
72.167
1.00
49.62
ATOM
160
CG
GLU
102
27.168
−26.621
72.070
1.00
55.61
ATOM
161
CD
GLU
102
28.245
−25.679
72.588
1.00
59.03
ATOM
162
OE1
GLU
102
29.297
−26.166
73.077
1.00
59.85
ATOM
163
OE2
GLU
102
28.034
−24.448
72.489
1.00
60.10
ATOM
164
C
GLU
102
23.869
−25.627
73.715
1.00
45.67
ATOM
165
O
GLU
102
23.278
−24.568
73.567
1.00
45.84
ATOM
166
N
GLN
103
23.244
−26.764
73.982
1.00
45.79
ATOM
167
CA
GLN
103
21.795
−26.786
74.101
1.00
47.31
ATOM
168
CB
GLN
103
21.271
−28.220
74.156
1.00
48.93
ATOM
169
CG
GLN
103
19.750
−28.313
74.345
1.00
52.63
ATOM
170
CD
GLN
103
18.929
−27.662
73.216
1.00
53.89
ATOM
171
OE1
GLN
103
17.703
−27.566
73.309
1.00
54.70
ATOM
172
NE2
GLN
103
19.600
−27.222
72.154
1.00
52.85
ATOM
173
C
GLN
103
21.416
−26.066
75.363
1.00
47.02
ATOM
174
O
GLN
103
20.494
−25.260
75.390
1.00
46.84
ATOM
175
N
MET
104
22.146
−26.369
76.418
1.00
48.58
ATOM
176
CA
MET
104
21.902
−25.752
77.703
1.00
49.89
ATOM
177
CB
MET
104
22.985
−26.182
78.694
1.00
52.33
ATOM
178
CG
MET
104
22.741
−25.743
80.137
1.00
56.81
ATOM
179
SD
MET
104
22.286
−27.119
81.216
1.00
60.04
ATOM
180
CE
MET
104
20.594
−27.574
80.517
1.00
58.09
ATOM
181
C
MET
104
21.975
−24.255
77.483
1.00
49.53
ATOM
182
O
MET
104
20.998
−23.535
77.676
1.00
50.52
ATOM
183
N
HIS
105
23.146
−23.808
77.048
1.00
48.30
ATOM
184
CA
HIS
105
23.409
−22.403
76.807
1.00
47.10
ATOM
185
CB
HIS
105
24.712
−22.250
76.031
1.00
46.50
ATOM
186
CG
HIS
105
25.181
−20.836
75.913
1.00
45.38
ATOM
187
CD2
HIS
105
25.468
−20.082
74.828
1.00
44.97
ATOM
188
ND1
HIS
105
25.431
−20.044
77.010
1.00
45.09
ATOM
189
CE1
HIS
105
25.855
−18.859
76.607
1.00
45.28
ATOM
190
NE2
HIS
105
25.887
−18.858
75.289
1.00
45.84
ATOM
191
C
HIS
105
22.306
−21.664
76.077
1.00
47.03
ATOM
192
O
HIS
105
22.185
−20.458
76.222
1.00
47.98
ATOM
193
N
GLU
106
21.506
−22.362
75.283
1.00
47.46
ATOM
194
CA
GLU
106
20.439
−21.680
74.564
1.00
48.81
ATOM
195
CB
GLU
106
20.203
−22.323
73.203
1.00
51.42
ATOM
196
CG
GLU
106
21.432
−22.305
72.320
1.00
57.65
ATOM
197
CD
GLU
106
21.126
−22.632
70.870
1.00
61.26
ATOM
198
OE1
GLU
106
20.441
−23.656
70.619
1.00
63.05
ATOM
199
OE2
GLU
106
21.583
−21.866
69.985
1.00
62.41
ATOM
200
C
GLU
106
19.153
−21.679
75.356
1.00
48.72
ATOM
201
O
GLU
106
18.369
−20.731
75.281
1.00
47.67
ATOM
202
N
ASP
107
18.928
−22.747
76.109
1.00
49.07
ATOM
203
CA
ASP
107
17.733
−22.828
76.921
1.00
49.88
ATOM
204
CB
ASP
107
17.606
−24.210
77.535
1.00
52.08
ATOM
205
CG
ASP
107
17.469
−25.283
76.484
1.00
55.84
ATOM
206
OD1
ASP
107
16.638
−25.099
75.569
1.00
56.69
ATOM
207
OD2
ASP
107
18.186
−26.304
76.566
1.00
58.55
ATOM
208
C
ASP
107
17.834
−21.775
78.000
1.00
49.32
ATOM
209
O
ASP
107
16.845
−21.127
78.340
1.00
50.32
ATOM
210
N
ILE
108
19.043
−21.595
78.524
1.00
48.00
ATOM
211
CA
ILE
108
19.285
−20.600
79.562
1.00
46.04
ATOM
212
CB
ILE
108
20.713
−20.686
80.102
1.00
45.64
ATOM
213
CG2
ILE
108
20.891
−19.691
81.234
1.00
43.75
ATOM
214
CG1
ILE
108
21.024
−22.119
80.550
1.00
46.19
ATOM
215
CD1
ILE
108
20.330
−22.579
81.803
1.00
46.61
ATOM
216
C
ILE
108
19.082
−19.204
78.979
1.00
45.89
ATOM
217
O
ILE
108
18.185
−18.483
79.396
1.00
47.43
ATOM
218
N
CYS
109
19.913
−18.824
78.015
1.00
44.32
ATOM
219
CA
CYS
109
19.773
−17.518
77.413
1.00
43.51
ATOM
220
C
CYS
109
18.334
−17.218
77.154
1.00
41.47
ATOM
221
O
CYS
109
17.860
−16.135
77.471
1.00
40.35
ATOM
222
CB
CYS
109
20.550
−17.422
76.110
1.00
46.91
ATOM
223
SG
CYS
109
22.213
−16.826
76.488
1.00
54.67
ATOM
224
N
SER
110
17.643
−18.198
76.585
1.00
41.43
ATOM
225
CA
SER
110
16.227
−18.094
76.252
1.00
42.22
ATOM
226
CB
SER
110
15.780
−19.377
75.551
1.00
43.14
ATOM
227
OG
SER
110
14.365
−19.448
75.485
1.00
46.83
ATOM
228
C
SER
110
15.347
−17.839
77.473
1.00
41.93
ATOM
229
O
SER
110
14.414
−17.037
77.438
1.00
40.88
ATOM
230
N
LEU
111
15.646
−18.534
78.557
1.00
42.29
ATOM
231
CA
LEU
111
14.881
−18.369
79.773
1.00
43.38
ATOM
232
CB
LEU
111
15.370
−19.376
80.807
1.00
41.89
ATOM
233
CG
LEU
111
14.309
−19.802
81.813
1.00
42.18
ATOM
234
CD1
LEU
111
13.052
−20.245
81.083
1.00
42.84
ATOM
235
CD2
LEU
111
14.863
−20.926
82.659
1.00
43.66
ATOM
236
C
LEU
111
15.061
−16.935
80.279
1.00
45.09
ATOM
237
O
LEU
111
14.095
−16.253
80.633
1.00
44.96
ATOM
238
N
TRP
112
16.307
−16.476
80.290
1.00
46.31
ATOM
239
CA
TRP
112
16.613
−15.131
80.744
1.00
48.17
ATOM
240
CB
TRP
112
18.126
−14.922
80.779
1.00
49.91
ATOM
241
CG
TRP
112
18.747
−15.516
82.010
1.00
52.44
ATOM
242
CD2
TRP
112
19.544
−14.840
82.984
1.00
53.45
ATOM
243
CE2
TRP
112
19.851
−15.778
83.999
1.00
53.54
ATOM
244
CE3
TRP
112
20.031
−13.532
83.102
1.00
54.72
ATOM
245
CD1
TRP
112
18.613
−16.796
82.453
1.00
52.57
ATOM
246
NE1
TRP
112
19.269
−16.964
83.647
1.00
51.79
ATOM
247
CZ2
TRP
112
20.619
−15.454
85.121
1.00
55.71
ATOM
248
CZ3
TRP
112
20.797
−13.204
84.217
1.00
56.51
ATOM
249
CH2
TRP
112
21.083
−14.165
85.215
1.00
57.71
ATOM
250
C
TRP
112
15.951
−14.044
79.914
1.00
49.45
ATOM
251
O
TRP
112
15.497
−13.047
80.459
1.00
50.46
ATOM
252
N
ASP
113
15.889
−14.222
78.603
1.00
50.27
ATOM
253
CA
ASP
113
15.257
−13.220
77.765
1.00
51.73
ATOM
254
CB
ASP
113
15.386
−13.594
76.291
1.00
53.23
ATOM
255
CG
ASP
113
16.821
−13.541
75.807
1.00
55.73
ATOM
256
OD1
ASP
113
17.504
−12.529
76.078
1.00
56.27
ATOM
257
OD2
ASP
113
17.270
−14.506
75.152
1.00
57.05
ATOM
258
C
ASP
113
13.788
−13.064
78.125
1.00
52.99
ATOM
259
O
ASP
113
13.250
−11.953
78.091
1.00
52.81
ATOM
260
N
GLN
114
13.144
−14.173
78.483
1.00
54.06
ATOM
261
CA
GLN
114
11.727
−14.145
78.837
1.00
54.67
ATOM
262
CB
GLN
114
11.018
−15.408
78.318
1.00
56.60
ATOM
263
CG
GLN
114
11.793
−16.710
78.507
1.00
61.03
ATOM
264
CD
GLN
114
11.135
−17.906
77.812
1.00
63.04
ATOM
265
OE1
GLN
114
10.062
−18.362
78.210
1.00
64.12
ATOM
266
NE2
GLN
114
11.780
−18.411
76.764
1.00
63.49
ATOM
267
C
GLN
114
11.441
−13.953
80.321
1.00
53.71
ATOM
268
O
GLN
114
10.316
−14.158
80.766
1.00
54.68
ATOM
269
N
SER
115
12.449
−13.547
81.086
1.00
52.50
ATOM
270
CA
SER
115
12.265
−13.308
82.519
1.00
51.69
ATOM
271
CB
SER
115
13.038
−14.336
83.348
1.00
51.04
ATOM
272
OG
SER
115
12.621
−15.652
83.056
1.00
52.93
ATOM
273
C
SER
115
12.746
−11.913
82.901
1.00
51.57
ATOM
274
O
SER
115
12.011
−11.142
83.520
1.00
52.69
ATOM
275
N
LEU
116
13.989
−11.604
82.532
1.00
49.90
ATOM
276
CA
LEU
116
14.603
−10.315
82.825
1.00
48.45
ATOM
277
CB
LEU
116
16.022
−10.529
83.343
1.00
47.47
ATOM
278
CG
LEU
116
16.268
−10.161
84.806
1.00
48.17
ATOM
279
CD1
LEU
116
17.715
−10.461
85.176
1.00
47.96
ATOM
280
CD2
LEU
116
15.955
−8.686
85.019
1.00
47.70
ATOM
281
C
LEU
116
14.645
−9.431
81.581
1.00
48.28
ATOM
282
O
LEU
116
15.644
−9.414
80.858
1.00
48.83
ATOM
283
N
LYS
117
13.571
−8.682
81.345
1.00
46.85
ATOM
284
CA
LYS
117
13.479
−7.817
80.170
1.00
45.19
ATOM
285
CB
LYS
117
12.012
−7.662
79.768
1.00
45.35
ATOM
286
CG
LYS
117
11.377
−8.958
79.341
1.00
45.38
ATOM
287
CD
LYS
117
9.987
−8.733
78.809
1.00
45.69
ATOM
288
CE
LYS
117
9.621
−9.864
77.882
1.00
45.39
ATOM
289
NZ
LYS
117
10.704
−10.041
76.876
1.00
44.68
ATOM
290
C
LYS
117
14.100
−6.440
80.351
1.00
43.15
ATOM
291
O
LYS
117
14.002
−5.846
81.410
1.00
43.84
ATOM
292
N
PRO
118
14.764
−5.920
79.315
1.00
41.84
ATOM
293
CD
PRO
118
15.467
−6.711
78.301
1.00
41.18
ATOM
294
CA
PRO
118
15.377
−4.594
79.428
1.00
42.68
ATOM
295
CB
PRO
118
16.611
−4.708
78.532
1.00
41.64
ATOM
296
CG
PRO
118
16.852
−6.184
78.446
1.00
41.32
ATOM
297
C
PRO
118
14.452
−3.444
78.977
1.00
44.00
ATOM
298
O
PRO
118
13.547
−3.631
78.155
1.00
43.14
ATOM
299
N
CYS
119
14.688
−2.258
79.528
1.00
44.26
ATOM
300
CA
CYS
119
13.911
−1.082
79.177
1.00
45.33
ATOM
301
C
CYS
119
14.328
−0.688
77.776
1.00
44.84
ATOM
302
O
CYS
119
13.536
−0.157
76.996
1.00
45.02
ATOM
303
CB
CYS
119
14.212
0.059
80.148
1.00
48.41
ATOM
304
SG
CYS
119
14.000
−0.390
81.904
1.00
55.41
ATOM
305
N
VAL
120
15.595
−0.946
77.476
1.00
43.63
ATOM
306
CA
VAL
120
16.165
−0.669
76.166
1.00
42.72
ATOM
307
CB
VAL
120
16.807
0.719
76.110
1.00
40.94
ATOM
308
CG1
VAL
120
17.494
0.914
74.784
1.00
38.51
ATOM
309
CG2
VAL
120
15.740
1.773
76.293
1.00
40.48
ATOM
310
C
VAL
120
17.217
−1.734
75.897
1.00
43.68
ATOM
311
O
VAL
120
17.932
−2.162
76.811
1.00
42.94
ATOM
312
N
LYS
121
17.292
−2.168
74.643
1.00
44.39
ATOM
313
CA
LYS
121
18.232
−3.197
74.237
1.00
45.78
ATOM
314
CB
LYS
121
17.498
−4.530
74.119
1.00
46.75
ATOM
315
CG
LYS
121
18.292
−5.667
73.498
1.00
48.39
ATOM
316
CD
LYS
121
17.477
−6.942
73.525
1.00
49.47
ATOM
317
CE
LYS
121
18.214
−8.075
72.855
1.00
52.19
ATOM
318
NZ
LYS
121
17.391
−9.321
72.815
1.00
54.57
ATOM
319
C
LYS
121
18.834
−2.829
72.897
1.00
46.81
ATOM
320
O
LYS
121
18.119
−2.708
71.913
1.00
47.70
ATOM
321
N
LEU
122
20.146
−2.641
72.864
1.00
48.66
ATOM
322
CA
LEU
122
20.828
−2.293
71.629
1.00
51.53
ATOM
323
CB
LEU
122
21.795
−1.138
71.841
1.00
50.96
ATOM
324
CG
LEU
122
21.169
0.187
72.235
1.00
51.52
ATOM
325
CD1
LEU
122
22.202
1.272
72.015
1.00
52.75
ATOM
326
CD2
LEU
122
19.930
0.468
71.403
1.00
51.31
ATOM
327
C
LEU
122
21.613
−3.454
71.075
1.00
54.29
ATOM
328
O
LEU
122
22.385
−4.069
71.794
1.00
55.82
ATOM
329
N
CYS
123
21.422
−3.756
69.796
1.00
57.66
ATOM
330
CA
CYS
123
22.156
−4.844
69.161
1.00
61.99
ATOM
331
C
CYS
123
22.651
−4.401
67.790
1.00
65.95
ATOM
332
O
CYS
123
21.868
−3.977
66.952
1.00
66.42
ATOM
333
CB
CYS
123
21.261
−6.068
69.001
1.00
61.14
ATOM
334
SG
CYS
123
20.636
−6.863
70.520
1.00
64.65
ATOM
335
N
PRO
124
23.962
−4.486
67.543
1.00
70.34
ATOM
336
CD
PRO
124
25.032
−4.644
68.538
1.00
71.39
ATOM
337
CA
PRO
124
24.526
−4.079
66.255
1.00
74.44
ATOM
338
CB
PRO
124
25.915
−3.586
66.640
1.00
73.49
ATOM
339
CG
PRO
124
26.298
−4.577
67.678
1.00
72.11
ATOM
340
C
PRO
124
24.600
−5.151
65.170
1.00
78.68
ATOM
341
O
PRO
124
25.007
−6.289
65.435
1.00
78.97
ATOM
342
N
LEU
125
24.216
−4.754
63.952
1.00
83.43
ATOM
343
CA
LEU
125
24.246
−5.602
62.755
1.00
87.97
ATOM
344
CB
LEU
125
22.826
−5.802
62.199
1.00
85.90
ATOM
345
CG
LEU
125
22.682
−6.595
60.892
1.00
85.01
ATOM
346
CD1
LEU
125
23.501
−7.878
60.933
1.00
84.72
ATOM
347
CD2
LEU
125
21.223
−6.908
60.673
1.00
84.26
ATOM
348
C
LEU
125
25.136
−4.880
61.723
1.00
91.79
ATOM
349
O
LEU
125
24.645
−4.294
60.751
1.00
92.07
ATOM
350
N
CYS
126
26.449
−4.932
61.963
1.00
95.81
ATOM
351
CA
CYS
126
27.456
−4.274
61.128
1.00
99.93
ATOM
352
C
CYS
126
27.478
−4.610
59.639
1.00
101.72
ATOM
353
O
CYS
126
26.500
−5.115
59.075
1.00
101.70
ATOM
354
CB
CYS
126
28.860
−4.525
61.702
1.00
101.65
ATOM
355
SG
CYS
126
29.830
−3.024
62.094
1.00
105.44
ATOM
356
N
VAL
127
28.627
−4.317
59.026
1.00
103.91
ATOM
357
CA
VAL
127
28.873
−4.528
57.601
1.00
105.90
ATOM
358
CB
VAL
127
29.149
−6.029
57.278
1.00
105.47
ATOM
359
CG1
VAL
127
29.583
−6.188
55.822
1.00
104.28
ATOM
360
CG2
VAL
127
30.240
−6.563
58.196
1.00
104.81
ATOM
361
C
VAL
127
27.668
−4.011
56.817
1.00
107.53
ATOM
362
O
VAL
127
27.187
−2.905
57.086
1.00
107.44
ATOM
363
N
GLY
128
27.171
−4.801
55.869
1.00
108.79
ATOM
364
CA
GLY
128
26.041
−4.358
55.076
1.00
110.07
ATOM
365
C
GLY
128
26.390
−3.033
54.422
1.00
111.37
ATOM
366
O
GLY
128
25.543
−2.144
54.318
1.00
111.70
ATOM
367
N
ALA
129
27.653
−2.909
54.007
1.00
112.10
ATOM
368
CA
ALA
129
28.187
−1.712
53.350
1.00
112.06
ATOM
369
CB
ALA
129
27.246
−1.268
52.213
1.00
112.16
ATOM
370
C
ALA
129
28.491
−0.520
54.272
1.00
111.66
ATOM
371
O
ALA
129
27.895
0.551
54.125
1.00
111.99
ATOM
372
N
GLY
194
29.418
−0.709
55.215
1.00
110.69
ATOM
373
CA
GLY
194
29.815
0.358
56.129
1.00
108.83
ATOM
374
C
GLY
194
28.806
0.894
57.136
1.00
107.51
ATOM
375
O
GLY
194
29.136
1.040
58.316
1.00
106.82
ATOM
376
N
SER
195
27.596
1.212
56.672
1.00
106.32
ATOM
377
CA
SER
195
26.529
1.737
57.529
1.00
104.42
ATOM
378
CB
SER
195
25.342
2.211
56.684
1.00
104.28
ATOM
379
OG
SER
195
25.728
3.205
55.752
1.00
103.83
ATOM
380
C
SER
195
26.050
0.664
58.497
1.00
103.36
ATOM
381
O
SER
195
24.927
0.164
58.381
1.00
103.62
ATOM
382
N
CYS
196
26.917
0.317
59.446
1.00
101.48
ATOM
383
CA
CYS
196
26.631
−0.696
60.461
1.00
98.25
ATOM
384
C
CYS
196
25.391
−0.331
61.275
1.00
93.82
ATOM
385
O
CYS
196
25.496
0.258
62.352
1.00
93.50
ATOM
386
CB
CYS
196
27.846
−0.843
61.390
1.00
100.91
ATOM
387
SG
CYS
196
29.301
−1.683
60.659
1.00
104.77
ATOM
388
N
ASN
197
24.219
−0.688
60.758
1.00
88.40
ATOM
389
CA
ASN
197
22.973
−0.380
61.444
1.00
82.77
ATOM
390
CB
ASN
197
21.770
−0.728
60.566
1.00
85.03
ATOM
391
CG
ASN
197
21.187
0.494
59.868
1.00
87.21
ATOM
392
OD1
ASN
197
20.801
1.465
60.529
1.00
88.02
ATOM
393
ND2
ASN
197
21.120
0.450
58.539
1.00
88.02
ATOM
394
C
ASN
197
22.863
−1.088
62.780
1.00
77.50
ATOM
395
O
ASN
197
23.334
−2.210
62.943
1.00
77.29
ATOM
396
N
THR
198
22.227
−0.413
63.730
1.00
71.01
ATOM
397
CA
THR
198
22.048
−0.929
65.075
1.00
63.96
ATOM
398
CB
THR
198
22.715
0.006
66.085
1.00
64.25
ATOM
399
OG1
THR
198
24.118
0.085
65.802
1.00
64.31
ATOM
400
CG2
THR
198
22.496
−0.496
67.500
1.00
64.07
ATOM
401
C
THR
198
20.575
−1.056
65.427
1.00
58.97
ATOM
402
O
THR
198
19.859
−0.065
65.448
1.00
58.60
ATOM
403
N
SER
199
20.136
−2.279
65.709
1.00
53.41
ATOM
404
CA
SER
199
18.747
−2.559
66.067
1.00
48.39
ATOM
405
CB
SER
199
18.470
−4.051
65.915
1.00
47.89
ATOM
406
OG
SER
199
17.306
−4.425
66.627
1.00
48.16
ATOM
407
C
SER
199
18.439
−2.134
67.495
1.00
45.34
ATOM
408
O
SER
199
19.174
−2.470
68.403
1.00
45.45
ATOM
409
N
VAL
200
17.340
−1.414
67.691
1.00
42.99
ATOM
410
CA
VAL
200
16.955
−0.932
69.016
1.00
40.63
ATOM
411
CB
VAL
200
16.927
0.610
69.046
1.00
39.79
ATOM
412
CG1
VAL
200
16.500
1.098
70.404
1.00
39.65
ATOM
413
CG2
VAL
200
18.290
1.164
68.702
1.00
38.60
ATOM
414
C
VAL
200
15.583
−1.440
69.449
1.00
40.29
ATOM
415
O
VAL
200
14.629
−1.400
68.678
1.00
40.35
ATOM
416
N
ILE
201
15.482
−1.905
70.689
1.00
40.20
ATOM
417
CA
ILE
201
14.217
−2.417
71.219
1.00
41.32
ATOM
418
CB
ILE
201
14.249
−3.956
71.405
1.00
42.65
ATOM
419
CG2
ILE
201
12.921
−4.441
71.989
1.00
41.02
ATOM
420
CG1
ILE
201
14.543
−4.646
70.070
1.00
43.17
ATOM
421
CD1
ILE
201
14.834
−6.135
70.211
1.00
44.46
ATOM
422
C
ILE
201
13.874
−1.810
72.577
1.00
41.94
ATOM
423
O
ILE
201
14.654
−1.896
73.532
1.00
41.41
ATOM
424
N
THR
202
12.690
−1.214
72.657
1.00
41.95
ATOM
425
CA
THR
202
12.226
−0.601
73.889
1.00
42.08
ATOM
426
CB
THR
202
11.969
0.892
73.696
1.00
41.25
ATOM
427
OG1
THR
202
13.082
1.490
73.027
1.00
40.91
ATOM
428
CG2
THR
202
11.788
1.560
75.031
1.00
41.52
ATOM
429
C
THR
202
10.918
−1.251
74.318
1.00
43.20
ATOM
430
O
THR
202
9.948
−1.241
73.563
1.00
43.24
ATOM
431
N
GLN
203
10.890
−1.818
75.524
1.00
44.57
ATOM
432
CA
GLN
203
9.679
−2.464
76.037
1.00
45.88
ATOM
433
CB
GLN
203
9.752
−3.978
75.850
1.00
45.18
ATOM
434
CG
GLN
203
10.718
−4.635
76.792
1.00
46.99
ATOM
435
CD
GLN
203
11.663
−5.579
76.093
1.00
48.26
ATOM
436
OE1
GLN
203
11.253
−6.602
75.541
1.00
47.41
ATOM
437
NE2
GLN
203
12.945
−5.236
76.109
1.00
49.20
ATOM
438
C
GLN
203
9.526
−2.169
77.515
1.00
46.24
ATOM
439
O
GLN
203
10.416
−1.575
78.126
1.00
46.33
ATOM
440
N
ALA
204
8.395
−2.576
78.086
1.00
46.69
ATOM
441
CA
ALA
204
8.169
−2.376
79.510
1.00
47.75
ATOM
442
CB
ALA
204
6.754
−2.731
79.869
1.00
47.77
ATOM
443
C
ALA
204
9.155
−3.326
80.193
1.00
49.20
ATOM
444
O
ALA
204
9.282
−4.492
79.799
1.00
50.45
ATOM
445
N
CYS
205
9.854
−2.830
81.209
1.00
49.03
ATOM
446
CA
CYS
205
10.870
−3.618
81.895
1.00
47.82
ATOM
447
C
CYS
205
10.596
−3.914
83.372
1.00
47.00
ATOM
448
O
CYS
205
11.342
−3.464
84.244
1.00
47.48
ATOM
449
CB
CYS
205
12.214
−2.899
81.749
1.00
49.40
ATOM
450
SG
CYS
205
12.089
−1.097
82.038
1.00
52.40
ATOM
451
N
PRO
206
9.535
−4.692
83.671
1.00
45.36
ATOM
452
CD
PRO
206
8.592
−5.258
82.690
1.00
44.00
ATOM
453
CA
PRO
206
9.142
−5.069
85.037
1.00
43.93
ATOM
454
CB
PRO
206
8.083
−6.135
84.797
1.00
42.82
ATOM
455
CG
PRO
206
7.423
−5.660
83.552
1.00
42.86
ATOM
456
C
PRO
206
10.294
−5.603
85.890
1.00
43.70
ATOM
457
O
PRO
206
11.013
−6.495
85.458
1.00
43.27
ATOM
458
N
LYS
207
10.471
−5.059
87.094
1.00
44.28
ATOM
459
CA
LYS
207
11.533
−5.521
87.992
1.00
45.36
ATOM
460
CB
LYS
207
11.664
−4.626
89.235
1.00
43.66
ATOM
461
CG
LYS
207
12.061
−3.179
89.019
1.00
42.40
ATOM
462
CD
LYS
207
13.436
−3.046
88.429
1.00
41.07
ATOM
463
CE
LYS
207
14.481
−3.725
89.264
1.00
40.58
ATOM
464
NZ
LYS
207
15.758
−3.685
88.510
1.00
40.89
ATOM
465
C
LYS
207
11.157
−6.913
88.481
1.00
47.60
ATOM
466
O
LYS
207
10.126
−7.086
89.126
1.00
49.38
ATOM
467
N
VAL
208
11.975
−7.910
88.185
1.00
49.19
ATOM
468
CA
VAL
208
11.669
−9.248
88.654
1.00
50.40
ATOM
469
CB
VAL
208
11.317
−10.192
87.512
1.00
49.17
ATOM
470
CG1
VAL
208
10.947
−11.548
88.072
1.00
48.47
ATOM
471
CG2
VAL
208
10.171
−9.621
86.720
1.00
49.94
ATOM
472
C
VAL
208
12.867
−9.800
89.379
1.00
52.48
ATOM
473
O
VAL
208
13.950
−9.895
88.820
1.00
53.30
ATOM
474
N
SER
209
12.667
−10.153
90.638
1.00
55.82
ATOM
475
CA
SER
209
13.744
−10.701
91.442
1.00
59.23
ATOM
476
CB
SER
209
14.271
−9.657
92.433
1.00
60.00
ATOM
477
OG
SER
209
13.294
−9.300
93.397
1.00
59.59
ATOM
478
C
SER
209
13.251
−11.912
92.205
1.00
60.56
ATOM
479
O
SER
209
12.328
−11.819
93.015
1.00
61.51
ATOM
480
N
PHE
210
13.863
−13.054
91.927
1.00
61.88
ATOM
481
CA
PHE
210
13.509
−14.293
92.596
1.00
62.55
ATOM
482
CB
PHE
210
12.163
−14.831
92.088
1.00
62.36
ATOM
483
CG
PHE
210
12.173
−15.247
90.645
1.00
62.80
ATOM
484
CD1
PHE
210
12.312
−14.303
89.634
1.00
63.22
ATOM
485
CD2
PHE
210
12.044
−16.588
90.295
1.00
63.02
ATOM
486
CE1
PHE
210
12.321
−14.690
88.294
1.00
62.99
ATOM
487
CE2
PHE
210
12.052
−16.980
88.957
1.00
63.02
ATOM
488
CZ
PHE
210
12.191
−16.027
87.956
1.00
62.16
ATOM
489
C
PHE
210
14.624
−15.285
92.317
1.00
62.59
ATOM
490
O
PHE
210
15.231
−15.266
91.245
1.00
62.81
ATOM
491
N
GLU
211
14.908
−16.138
93.291
1.00
62.66
ATOM
492
CA
GLU
211
15.963
−17.120
93.127
1.00
62.85
ATOM
493
CB
GLU
211
16.274
−17.768
94.490
1.00
63.27
ATOM
494
CG
GLU
211
17.354
−16.985
95.278
1.00
65.06
ATOM
495
CD
GLU
211
17.291
−17.160
96.800
1.00
65.99
ATOM
496
OE1
GLU
211
17.055
−18.299
97.267
1.00
66.91
ATOM
497
OE2
GLU
211
17.497
−16.153
97.528
1.00
63.93
ATOM
498
C
GLU
211
15.645
−18.161
92.036
1.00
61.85
ATOM
499
O
GLU
211
14.538
−18.703
91.965
1.00
61.07
ATOM
500
N
PRO
212
16.617
−18.406
91.136
1.00
60.73
ATOM
501
CD
PRO
212
17.853
−17.606
91.033
1.00
60.13
ATOM
502
CA
PRO
212
16.529
−19.355
90.019
1.00
60.07
ATOM
503
CB
PRO
212
17.865
−19.151
89.295
1.00
60.56
ATOM
504
CG
PRO
212
18.190
−17.724
89.579
1.00
58.99
ATOM
505
C
PRO
212
16.318
−20.824
90.424
1.00
59.13
ATOM
506
O
PRO
212
17.062
−21.371
91.241
1.00
58.14
ATOM
507
N
ILE
213
15.308
−21.454
89.834
1.00
58.39
ATOM
508
CA
ILE
213
14.999
−22.851
90.111
1.00
57.51
ATOM
509
CB
ILE
213
13.582
−23.226
89.634
1.00
57.45
ATOM
510
CG2
ILE
213
12.936
−24.123
90.645
1.00
58.00
ATOM
511
CG1
ILE
213
12.716
−21.978
89.461
1.00
58.13
ATOM
512
CD1
ILE
213
12.426
−21.230
90.750
1.00
58.27
ATOM
513
C
ILE
213
15.995
−23.705
89.330
1.00
57.45
ATOM
514
O
ILE
213
16.398
−23.335
88.225
1.00
57.51
ATOM
515
N
PRO
214
16.406
−24.863
89.888
1.00
56.69
ATOM
516
CD
PRO
214
16.153
−25.380
91.240
1.00
55.47
ATOM
517
CA
PRO
214
17.361
−25.729
89.193
1.00
55.78
ATOM
518
CB
PRO
214
17.614
−26.845
90.197
1.00
54.06
ATOM
519
CG
PRO
214
17.405
−26.184
91.489
1.00
54.24
ATOM
520
C
PRO
214
16.789
−26.257
87.894
1.00
56.50
ATOM
521
O
PRO
214
15.620
−26.637
87.820
1.00
55.06
ATOM
522
N
ILE
215
17.640
−26.271
86.878
1.00
58.07
ATOM
523
CA
ILE
215
17.286
−26.745
85.555
1.00
58.99
ATOM
524
CB
ILE
215
17.892
−25.815
84.461
1.00
60.28
ATOM
525
CG2
ILE
215
17.752
−26.442
83.088
1.00
61.12
ATOM
526
CG1
ILE
215
17.218
−24.435
84.499
1.00
61.06
ATOM
527
CD1
ILE
215
15.713
−24.448
84.230
1.00
60.70
ATOM
528
C
ILE
215
17.846
−28.153
85.391
1.00
59.41
ATOM
529
O
ILE
215
18.987
−28.418
85.754
1.00
58.13
ATOM
530
N
HIS
216
17.019
−29.051
84.866
1.00
61.77
ATOM
531
CA
HIS
216
17.403
−30.436
84.617
1.00
63.93
ATOM
532
CB
HIS
216
16.393
−31.403
85.235
1.00
64.72
ATOM
533
CG
HIS
216
16.375
−31.414
86.730
1.00
67.28
ATOM
534
CD2
HIS
216
15.441
−30.977
87.609
1.00
67.94
ATOM
535
ND1
HIS
216
17.375
−31.987
87.483
1.00
68.72
ATOM
536
CE1
HIS
216
17.057
−31.908
88.766
1.00
68.43
ATOM
537
NE2
HIS
216
15.890
−31.300
88.868
1.00
69.02
ATOM
538
C
HIS
216
17.378
−30.655
83.105
1.00
65.39
ATOM
539
O
HIS
216
16.331
−30.504
82.474
1.00
65.51
ATOM
540
N
TYR
217
18.517
−31.002
82.517
1.00
66.95
ATOM
541
CA
TYR
217
18.562
−31.260
81.081
1.00
67.77
ATOM
542
CB
TYR
217
19.964
−30.971
80.530
1.00
69.80
ATOM
543
CG
TYR
217
20.183
−31.360
79.076
1.00
72.85
ATOM
544
CD1
TYR
217
20.066
−32.688
78.656
1.00
73.62
ATOM
545
CE1
TYR
217
20.306
−33.062
77.332
1.00
73.91
ATOM
546
CD2
TYR
217
20.543
−30.408
78.124
1.00
74.21
ATOM
547
CE2
TYR
217
20.787
−30.774
76.791
1.00
75.39
ATOM
548
CZ
TYR
217
20.664
−32.105
76.407
1.00
75.03
ATOM
549
OH
TYR
217
20.905
−32.476
75.101
1.00
75.25
ATOM
550
C
TYR
217
18.198
−32.726
80.881
1.00
67.53
ATOM
551
O
TYR
217
18.779
−33.611
81.512
1.00
66.37
ATOM
552
N
CYS
218
17.220
−32.977
80.021
1.00
68.26
ATOM
553
CA
CYS
218
16.801
−34.345
79.736
1.00
69.95
ATOM
554
C
CYS
218
17.146
−34.676
78.291
1.00
70.18
ATOM
555
O
CYS
218
17.368
−33.768
77.483
1.00
71.00
ATOM
556
CB
CYS
218
15.299
−34.515
79.952
1.00
70.79
ATOM
557
SG
CYS
218
14.717
−34.185
81.647
1.00
73.86
ATOM
558
N
ALA
219
17.190
−35.969
77.972
1.00
69.23
ATOM
559
CA
ALA
219
17.525
−36.418
76.622
1.00
67.68
ATOM
560
CB
ALA
219
17.950
−37.874
76.651
1.00
68.44
ATOM
561
C
ALA
219
16.367
−36.224
75.644
1.00
66.31
ATOM
562
O
ALA
219
15.224
−36.577
75.937
1.00
64.91
ATOM
563
N
PRO
220
16.657
−35.652
74.462
1.00
65.58
ATOM
564
CD
PRO
220
17.955
−35.074
74.079
1.00
65.63
ATOM
565
CA
PRO
220
15.657
−35.394
73.420
1.00
64.40
ATOM
566
CB
PRO
220
16.352
−34.386
72.500
1.00
64.51
ATOM
567
CG
PRO
220
17.515
−33.858
73.317
1.00
65.89
ATOM
568
C
PRO
220
15.298
−36.670
72.676
1.00
63.38
ATOM
569
O
PRO
220
16.095
−37.609
72.625
1.00
63.61
ATOM
570
N
ALA
221
14.104
−36.691
72.090
1.00
61.61
ATOM
571
CA
ALA
221
13.645
−37.852
71.345
1.00
59.16
ATOM
572
CB
ALA
221
12.397
−37.503
70.558
1.00
57.25
ATOM
573
C
ALA
221
14.751
−38.323
70.407
1.00
58.51
ATOM
574
O
ALA
221
15.303
−37.532
69.645
1.00
58.11
ATOM
575
N
GLY
222
15.092
−39.608
70.492
1.00
58.44
ATOM
576
CA
GLY
222
16.121
−40.163
69.632
1.00
58.13
ATOM
577
C
GLY
222
17.508
−40.316
70.229
1.00
58.27
ATOM
578
O
GLY
222
18.405
−40.830
69.560
1.00
57.97
ATOM
579
N
PHE
223
17.700
−39.888
71.475
1.00
58.69
ATOM
580
CA
PHE
223
19.020
−39.989
72.102
1.00
58.31
ATOM
581
CB
PHE
223
19.711
−38.625
72.073
1.00
59.64
ATOM
582
CG
PHE
223
20.030
−38.136
70.690
1.00
60.13
ATOM
583
CD1
PHE
223
19.032
−37.613
69.873
1.00
59.78
ATOM
584
CD2
PHE
223
21.330
−38.222
70.197
1.00
59.77
ATOM
585
CE1
PHE
223
19.323
−37.182
68.588
1.00
60.31
ATOM
586
CE2
PHE
223
21.632
−37.797
68.919
1.00
60.24
ATOM
587
CZ
PHE
223
20.626
−37.273
68.107
1.00
61.40
ATOM
588
C
PHE
223
19.052
−40.530
73.527
1.00
57.51
ATOM
589
O
PHE
223
18.016
−40.708
74.165
1.00
56.31
ATOM
590
N
ALA
224
20.261
−40.787
74.021
1.00
57.34
ATOM
591
CA
ALA
224
20.447
−41.309
75.373
1.00
58.31
ATOM
592
CB
ALA
224
20.842
−42.773
75.311
1.00
58.16
ATOM
593
C
ALA
224
21.517
−40.514
76.116
1.00
58.54
ATOM
594
O
ALA
224
22.404
−39.945
75.491
1.00
59.61
ATOM
595
N
ILE
225
21.436
−40.486
77.444
1.00
57.96
ATOM
596
CA
ILE
225
22.401
−39.751
78.255
1.00
57.94
ATOM
597
CB
ILE
225
21.699
−38.763
79.225
1.00
58.15
ATOM
598
CG2
ILE
225
22.734
−38.081
80.114
1.00
58.23
ATOM
599
CG1
ILE
225
20.904
−37.712
78.444
1.00
58.02
ATOM
600
CD1
ILE
225
20.136
−36.737
79.329
1.00
55.55
ATOM
601
C
ILE
225
23.278
−40.666
79.101
1.00
58.42
ATOM
602
O
ILE
225
22.794
−41.341
80.006
1.00
59.16
ATOM
603
N
LEU
226
24.572
−40.686
78.815
1.00
58.75
ATOM
604
CA
LEU
226
25.484
−41.509
79.597
1.00
59.39
ATOM
605
CB
LEU
226
26.569
−42.109
78.699
1.00
57.81
ATOM
606
CG
LEU
226
26.083
−42.866
77.461
1.00
56.08
ATOM
607
CD1
LEU
226
27.257
−43.550
76.802
1.00
55.05
ATOM
608
CD2
LEU
226
25.039
−43.886
77.838
1.00
55.26
ATOM
609
C
LEU
226
26.101
−40.612
80.667
1.00
60.63
ATOM
610
O
LEU
226
26.257
−39.412
80.453
1.00
60.94
ATOM
611
N
LYS
227
26.448
−41.197
81.810
1.00
62.31
ATOM
612
CA
LYS
227
27.022
−40.452
82.930
1.00
63.91
ATOM
613
CB
LYS
227
25.940
−40.230
84.000
1.00
63.10
ATOM
614
CG
LYS
227
26.440
−39.783
85.373
1.00
62.19
ATOM
615
CD
LYS
227
25.292
−39.708
86.391
1.00
61.38
ATOM
616
CE
LYS
227
25.767
−39.220
87.765
1.00
61.56
ATOM
617
NZ
LYS
227
24.653
−39.044
88.746
1.00
59.42
ATOM
618
C
LYS
227
28.208
−41.169
83.560
1.00
65.80
ATOM
619
O
LYS
227
28.038
−42.199
84.205
1.00
67.24
ATOM
620
N
CYS
228
29.409
−40.631
83.387
1.00
68.12
ATOM
621
CA
CYS
228
30.578
−41.262
83.983
1.00
70.64
ATOM
622
C
CYS
228
30.444
−41.156
85.496
1.00
70.41
ATOM
623
O
CYS
228
30.085
−40.107
86.019
1.00
70.19
ATOM
624
CB
CYS
228
31.871
−40.590
83.511
1.00
73.46
ATOM
625
SG
CYS
228
33.366
−41.502
84.026
1.00
78.70
ATOM
626
N
ASN
229
30.733
−42.243
86.200
1.00
71.33
ATOM
627
CA
ASN
229
30.600
−42.255
87.647
1.00
71.92
ATOM
628
CB
ASN
229
29.857
−43.508
88.082
1.00
72.45
ATOM
629
CG
ASN
229
28.411
−43.492
87.652
1.00
73.11
ATOM
630
OD1
ASN
229
27.647
−42.610
88.051
1.00
72.87
ATOM
631
ND2
ASN
229
28.022
−44.465
86.830
1.00
72.92
ATOM
632
C
ASN
229
31.867
−42.109
88.469
1.00
72.51
ATOM
633
O
ASN
229
31.785
−42.025
89.688
1.00
72.22
ATOM
634
N
ASN
230
33.033
−42.089
87.829
1.00
74.40
ATOM
635
CA
ASN
230
34.272
−41.910
88.582
1.00
76.62
ATOM
636
CB
ASN
230
35.455
−41.654
87.648
1.00
77.04
ATOM
637
CG
ASN
230
35.879
−42.887
86.894
1.00
78.06
ATOM
638
OD1
ASN
230
36.745
−42.818
86.020
1.00
78.68
ATOM
639
ND2
ASN
230
35.278
−44.024
87.232
1.00
78.86
ATOM
640
C
ASN
230
34.064
−40.685
89.458
1.00
77.81
ATOM
641
O
ASN
230
33.496
−39.687
89.010
1.00
78.44
ATOM
642
N
LYS
231
34.507
−40.754
90.706
1.00
79.00
ATOM
643
CA
LYS
231
34.338
−39.623
91.608
1.00
80.19
ATOM
644
CB
LYS
231
34.648
−40.048
93.049
1.00
81.06
ATOM
645
CG
LYS
231
33.678
−41.098
93.576
1.00
81.81
ATOM
646
CD
LYS
231
34.028
−41.600
94.968
1.00
82.80
ATOM
647
CE
LYS
231
33.081
−42.740
95.376
1.00
83.45
ATOM
648
NZ
LYS
231
33.385
−43.321
96.720
1.00
82.56
ATOM
649
C
LYS
231
35.235
−38.474
91.169
1.00
80.35
ATOM
650
O
LYS
231
35.008
−37.321
91.536
1.00
80.46
ATOM
651
N
THR
232
36.245
−38.803
90.368
1.00
80.83
ATOM
652
CA
THR
232
37.188
−37.817
89.843
1.00
81.48
ATOM
653
CB
THR
232
38.552
−37.900
90.545
1.00
81.81
ATOM
654
OG1
THR
232
38.381
−37.665
91.947
1.00
82.72
ATOM
655
CG2
THR
232
39.515
−36.865
89.965
1.00
81.15
ATOM
656
C
THR
232
37.399
−38.103
88.367
1.00
81.71
ATOM
657
O
THR
232
38.174
−38.987
87.998
1.00
82.58
ATOM
658
N
PHE
233
36.706
−37.350
87.526
1.00
81.77
ATOM
659
CA
PHE
233
36.807
−37.537
86.089
1.00
81.98
ATOM
660
CB
PHE
233
35.426
−37.881
85.532
1.00
80.95
ATOM
661
CG
PHE
233
35.448
−38.347
84.117
1.00
80.20
ATOM
662
CD1
PHE
233
36.242
−39.423
83.746
1.00
79.86
ATOM
663
CD2
PHE
233
34.675
−37.713
83.153
1.00
80.45
ATOM
664
CE1
PHE
233
36.269
−39.865
82.434
1.00
80.01
ATOM
665
CE2
PHE
233
34.692
−38.145
81.840
1.00
80.85
ATOM
666
CZ
PHE
233
35.493
−39.226
81.477
1.00
80.97
ATOM
667
C
PHE
233
37.351
−36.276
85.428
1.00
82.46
ATOM
668
O
PHE
233
36.918
−35.172
85.749
1.00
82.61
ATOM
669
N
ASN
234
38.304
−36.432
84.513
1.00
83.24
ATOM
670
CA
ASN
234
38.874
−35.271
83.841
1.00
84.16
ATOM
671
CB
ASN
234
40.354
−35.499
83.532
1.00
86.83
ATOM
672
CG
ASN
234
40.574
−36.548
82.469
1.00
90.05
ATOM
673
OD1
ASN
234
39.934
−36.527
81.421
1.00
91.19
ATOM
674
ND2
ASN
234
41.507
−37.457
82.725
1.00
92.74
ATOM
675
C
ASN
234
38.117
−34.914
82.559
1.00
83.56
ATOM
676
O
ASN
234
38.633
−34.196
81.697
1.00
83.14
ATOM
677
N
GLY
235
36.897
−35.433
82.444
1.00
82.91
ATOM
678
CA
GLY
235
36.049
−35.147
81.300
1.00
81.77
ATOM
679
C
GLY
235
36.479
−35.646
79.936
1.00
80.76
ATOM
680
O
GLY
235
35.687
−35.623
78.996
1.00
80.76
ATOM
681
N
THR
236
37.722
−36.095
79.808
1.00
79.92
ATOM
682
CA
THR
236
38.203
−36.583
78.521
1.00
78.75
ATOM
683
CB
THR
236
39.368
−35.722
77.992
1.00
79.46
ATOM
684
OG1
THR
236
39.526
−35.948
76.586
1.00
79.72
ATOM
685
CG2
THR
236
40.671
−36.091
78.698
1.00
79.62
ATOM
686
C
THR
236
38.676
−38.020
78.618
1.00
77.39
ATOM
687
O
THR
236
38.821
−38.564
79.706
1.00
77.35
ATOM
688
N
GLY
237
38.926
−38.628
77.469
1.00
76.80
ATOM
689
CA
GLY
237
39.390
−39.998
77.455
1.00
76.72
ATOM
690
C
GLY
237
38.283
−40.994
77.729
1.00
76.45
ATOM
691
O
GLY
237
37.106
−40.659
77.589
1.00
76.57
ATOM
692
N
PRO
238
38.634
−42.235
78.113
1.00
75.99
ATOM
693
CD
PRO
238
40.000
−42.777
78.002
1.00
75.67
ATOM
694
CA
PRO
238
37.689
−43.311
78.413
1.00
75.71
ATOM
695
CB
PRO
238
38.456
−44.544
77.980
1.00
75.43
ATOM
696
CG
PRO
238
39.824
−44.215
78.454
1.00
75.46
ATOM
697
C
PRO
238
37.247
−43.404
79.876
1.00
75.60
ATOM
698
O
PRO
238
38.014
−43.116
80.795
1.00
74.29
ATOM
699
N
CYS
239
35.996
−43.811
80.065
1.00
76.23
ATOM
700
CA
CYS
239
35.401
−43.978
81.386
1.00
77.64
ATOM
701
C
CYS
239
35.078
−45.462
81.561
1.00
77.75
ATOM
702
O
CYS
239
34.724
−46.151
80.602
1.00
77.99
ATOM
703
CB
CYS
239
34.114
−43.136
81.511
1.00
78.55
ATOM
704
SG
CYS
239
33.201
−43.307
83.092
1.00
79.98
ATOM
705
N
THR
240
35.205
−45.950
82.789
1.00
77.99
ATOM
706
CA
THR
240
34.936
−47.352
83.086
1.00
77.29
ATOM
707
CB
THR
240
36.156
−47.984
83.808
1.00
77.48
ATOM
708
OG1
THR
240
36.642
−47.088
84.817
1.00
77.79
ATOM
709
CG2
THR
240
37.276
−48.253
82.812
1.00
76.21
ATOM
710
C
THR
240
33.651
−47.555
83.914
1.00
76.52
ATOM
711
O
THR
240
32.878
−48.482
83.653
1.00
76.31
ATOM
712
N
ASN
241
33.427
−46.683
84.898
1.00
74.90
ATOM
713
CA
ASN
241
32.239
−46.740
85.760
1.00
72.80
ATOM
714
CB
ASN
241
32.617
−46.258
87.171
1.00
72.80
ATOM
715
CG
ASN
241
31.621
−46.691
88.241
1.00
72.83
ATOM
716
OD1
ASN
241
30.404
−46.657
88.031
1.00
73.02
ATOM
717
ND2
ASN
241
32.142
−47.079
89.402
1.00
71.56
ATOM
718
C
ASN
241
31.195
−45.797
85.132
1.00
71.45
ATOM
719
O
ASN
241
31.185
−44.601
85.419
1.00
70.59
ATOM
720
N
VAL
242
30.323
−46.333
84.278
1.00
69.95
ATOM
721
CA
VAL
242
29.319
−45.512
83.591
1.00
68.27
ATOM
722
CB
VAL
242
29.779
−45.171
82.153
1.00
68.44
ATOM
723
CG1
VAL
242
30.532
−46.343
81.548
1.00
68.10
ATOM
724
CG2
VAL
242
28.574
−44.842
81.286
1.00
68.72
ATOM
725
C
VAL
242
27.911
−46.091
83.494
1.00
66.92
ATOM
726
O
VAL
242
27.736
−47.279
83.258
1.00
67.05
ATOM
727
N
SER
243
26.908
−45.231
83.650
1.00
65.86
ATOM
728
CA
SER
243
25.513
−45.657
83.568
1.00
65.72
ATOM
729
CB
SER
243
24.911
−45.773
84.975
1.00
64.61
ATOM
730
OG
SER
243
25.167
−44.631
85.765
1.00
62.69
ATOM
731
C
SER
243
24.655
−44.729
82.700
1.00
65.75
ATOM
732
O
SER
243
25.138
−43.719
82.195
1.00
66.44
ATOM
733
N
THR
244
23.386
−45.089
82.523
1.00
65.22
ATOM
734
CA
THR
244
22.440
−44.307
81.722
1.00
64.94
ATOM
735
CB
THR
244
21.692
−45.202
80.714
1.00
65.14
ATOM
736
OG1
THR
244
22.448
−45.286
79.501
1.00
65.13
ATOM
737
CG2
THR
244
20.294
−44.655
80.422
1.00
64.17
ATOM
738
C
THR
244
21.408
−43.644
82.614
1.00
65.03
ATOM
739
O
THR
244
20.913
−44.262
83.550
1.00
66.14
ATOM
740
N
VAL
245
21.065
−42.397
82.310
1.00
64.75
ATOM
741
CA
VAL
245
20.089
−41.669
83.112
1.00
64.42
ATOM
742
CB
VAL
245
20.777
−40.574
83.939
1.00
64.72
ATOM
743
CG1
VAL
245
21.922
−41.172
84.732
1.00
64.56
ATOM
744
CG2
VAL
245
21.291
−39.477
83.019
1.00
65.00
ATOM
745
C
VAL
245
19.008
−41.016
82.264
1.00
64.37
ATOM
746
O
VAL
245
19.148
−40.887
81.052
1.00
62.59
ATOM
747
N
GLN
246
17.927
−40.600
82.910
1.00
65.67
ATOM
748
CA
GLN
246
16.839
−39.947
62.195
1.00
67.31
ATOM
749
CB
GLN
246
15.528
−40.083
82.972
1.00
69.55
ATOM
750
CG
GLN
246
15.009
−41.514
83.055
1.00
72.91
ATOM
751
CD
GLN
246
14.973
−42.189
81.691
1.00
74.79
ATOM
752
OE1
GLN
246
14.414
−41.645
80.737
1.00
76.33
ATOM
753
NE2
GLN
246
15.568
−43.381
81.593
1.00
74.80
ATOM
754
C
GLN
246
17.174
−38.477
81.991
1.00
67.14
ATOM
755
O
GLN
246
17.049
−37.952
80.887
1.00
67.40
ATOM
756
N
CYS
247
17.603
−37.819
83.064
1.00
67.11
ATOM
757
CA
CYS
247
17.981
−36.408
83.009
1.00
66.41
ATOM
758
C
CYS
247
19.173
−36.223
83.942
1.00
64.14
ATOM
759
O
CYS
247
19.394
−37.048
84.834
1.00
63.44
ATOM
760
CB
CYS
247
16.821
−35.516
83.465
1.00
68.57
ATOM
761
SG
CYS
247
15.192
−35.863
82.704
1.00
72.95
ATOM
762
N
THR
248
19.943
−35.155
83.736
1.00
61.65
ATOM
763
CA
THR
248
21.115
−34.882
84.571
1.00
58.60
ATOM
764
CB
THR
248
22.015
−33.789
83.953
1.00
58.51
ATOM
765
OG1
THR
248
21.401
−32.506
84.118
1.00
58.42
ATOM
766
CG2
THR
248
22.224
−34.048
82.472
1.00
57.39
ATOM
767
C
THR
248
20.649
−34.404
85.938
1.00
56.78
ATOM
768
O
THR
248
19.460
−34.479
86.248
1.00
56.77
ATOM
769
N
HIS
249
21.575
−33.914
86.759
1.00
54.48
ATOM
770
CA
HIS
249
21.204
−33.423
88.085
1.00
52.32
ATOM
771
CB
HIS
249
22.408
−33.455
89.036
1.00
50.67
ATOM
772
CG
HIS
249
23.557
−32.617
88.581
1.00
50.88
ATOM
773
CD2
HIS
249
23.960
−31.378
88.951
1.00
51.06
ATOM
774
ND1
HIS
249
24.418
−33.016
87.582
1.00
52.07
ATOM
775
CE1
HIS
249
25.300
−32.059
87.354
1.00
52.55
ATOM
776
NE2
HIS
249
25.043
−31.053
88.171
1.00
51.62
ATOM
777
C
HIS
249
20.648
−31.997
88.000
1.00
51.12
ATOM
778
O
HIS
249
20.672
−31.366
86.943
1.00
50.41
ATOM
779
N
GLY
250
20.120
−31.504
89.112
1.00
50.12
ATOM
780
CA
GLY
250
19.589
−30.158
89.128
1.00
48.39
ATOM
781
C
GLY
250
20.738
−29.188
89.013
1.00
47.71
ATOM
782
O
GLY
250
21.720
−29.274
89.754
1.00
47.82
ATOM
783
N
ILE
251
20.631
−28.262
88.075
1.00
47.08
ATOM
784
CA
ILE
251
21.692
−27.295
87.898
1.00
47.14
ATOM
785
CB
ILE
251
22.386
−27.494
86.533
1.00
46.53
ATOM
786
CG2
ILE
251
23.380
−26.363
86.268
1.00
46.08
ATOM
787
CG1
ILE
251
23.100
−28.845
86.534
1.00
46.01
ATOM
788
CD1
ILE
251
23.697
−29.231
85.209
1.00
46.76
ATOM
789
C
ILE
251
21.222
−25.856
88.050
1.00
47.08
ATOM
790
O
ILE
251
20.219
−25.439
87.479
1.00
46.45
ATOM
791
N
ARG
252
21.953
−25.114
88.868
1.00
47.74
ATOM
792
CA
ARG
252
21.651
−23.722
89.101
1.00
48.23
ATOM
793
CB
ARG
252
22.398
−23.209
90.335
1.00
49.56
ATOM
794
CG
ARG
252
21.642
−23.363
91.631
1.00
52.05
ATOM
795
CD
ARG
252
21.428
−24.816
91.987
1.00
55.46
ATOM
796
NE
ARG
252
20.534
−24.934
93.127
1.00
58.57
ATOM
797
CZ
ARG
252
20.800
−24.438
94.330
1.00
61.06
ATOM
798
NH1
ARG
252
21.942
−23.796
94.547
1.00
61.62
ATOM
799
NH2
ARG
252
19.917
−24.568
95.313
1.00
62.98
ATOM
800
C
ARG
252
22.125
−22.965
87.877
1.00
47.35
ATOM
801
O
ARG
252
23.322
−22.949
87.577
1.00
48.58
ATOM
802
N
PRO
253
21.194
−22.354
87.134
1.00
45.23
ATOM
803
CD
PRO
253
19.728
−22.423
87.233
1.00
44.55
ATOM
804
CA
PRO
253
21.595
−21.604
85.949
1.00
43.24
ATOM
805
CB
PRO
253
20.288
−21.483
85.179
1.00
42.38
ATOM
806
CG
PRO
253
19.293
−21.350
86.272
1.00
43.19
ATOM
807
C
PRO
253
22.182
−20.256
86.375
1.00
41.47
ATOM
808
O
PRO
253
21.744
−19.199
85.926
1.00
42.48
ATOM
809
N
VAL
254
23.179
−20.305
87.255
1.00
39.38
ATOM
810
CA
VAL
254
23.822
−19.092
87.751
1.00
37.91
ATOM
811
CB
VAL
254
24.819
−19.384
88.879
1.00
37.89
ATOM
812
CG1
VAL
254
25.491
−18.100
89.330
1.00
36.95
ATOM
813
CG2
VAL
254
24.107
−20.023
90.030
1.00
40.36
ATOM
814
C
VAL
254
24.589
−18.384
86.661
1.00
36.14
ATOM
815
O
VAL
254
25.346
−19.000
85.913
1.00
37.64
ATOM
816
N
VAL
255
24.399
−17.078
86.588
1.00
32.62
ATOM
817
CA
VAL
255
25.090
−16.278
85.607
1.00
30.04
ATOM
818
CB
VAL
255
24.103
−15.366
84.867
1.00
31.25
ATOM
819
CG1
VAL
255
24.783
−14.073
84.437
1.00
31.11
ATOM
820
CG2
VAL
255
23.571
−16.105
83.654
1.00
32.07
ATOM
821
C
VAL
255
26.165
−15.463
86.298
1.00
26.49
ATOM
822
O
VAL
255
25.878
−14.632
87.144
1.00
24.49
ATOM
823
N
SER
256
27.412
−15.706
85.931
1.00
24.46
ATOM
824
CA
SER
256
28.486
−14.982
86.556
1.00
23.46
ATOM
825
CB
SER
256
28.585
−15.389
88.010
1.00
22.73
ATOM
826
OG
SER
256
29.018
−16.727
88.096
1.00
21.19
ATOM
827
C
SER
256
29.846
−15.182
85.915
1.00
23.86
ATOM
828
O
SER
256
30.047
−16.034
85.038
1.00
22.73
ATOM
829
N
SER
257
30.787
−14.384
86.401
1.00
23.62
ATOM
830
CA
SER
257
32.159
−14.423
85.941
1.00
23.31
ATOM
831
CB
SER
257
32.559
−13.053
85.417
1.00
22.82
ATOM
832
OG
SER
257
32.592
−12.107
86.466
1.00
20.86
ATOM
833
C
SER
257
33.063
−14.804
87.106
1.00
23.53
ATOM
834
O
SER
257
32.629
−14.829
88.250
1.00
23.12
ATOM
835
N
GLN
258
34.313
−15.119
86.792
1.00
24.34
ATOM
836
CA
GLN
258
35.327
−15.475
87.785
1.00
26.23
ATOM
837
CB
GLN
258
35.699
−14.223
88.565
1.00
25.47
ATOM
838
CG
GLN
258
35.659
−13.014
87.684
1.00
25.81
ATOM
839
CD
GLN
258
36.430
−11.876
88.256
1.00
26.39
ATOM
840
OE1
GLN
258
36.368
−11.623
89.454
1.00
27.90
ATOM
841
NE2
GLN
258
37.163
−11.168
87.407
1.00
23.70
ATOM
842
C
GLN
258
34.995
−16.601
88.757
1.00
26.10
ATOM
843
O
GLN
258
35.661
−17.630
88.785
1.00
27.43
ATOM
844
N
LEU
259
33.965
−16.397
89.559
1.00
26.43
ATOM
845
CA
LEU
259
33.563
−17.382
90.538
1.00
25.71
ATOM
846
CB
LEU
259
33.304
−16.692
91.865
1.00
25.10
ATOM
847
CG
LEU
259
34.388
−15.692
92.261
1.00
24.45
ATOM
848
CD1
LEU
259
33.952
−14.868
93.466
1.00
20.24
ATOM
849
CD2
LEU
259
35.672
−16.457
92.530
1.00
26.19
ATOM
850
C
LEU
259
32.295
−18.068
90.083
1.00
26.56
ATOM
851
O
LEU
259
31.402
−17.423
89.533
1.00
27.02
ATOM
852
N
LEU
260
32.236
−19.377
90.310
1.00
26.59
ATOM
853
CA
LEU
260
31.076
−20.199
89.977
1.00
25.55
ATOM
854
CB
LEU
260
31.528
−21.570
89.490
1.00
21.73
ATOM
855
CG
LEU
260
32.353
−21.522
88.222
1.00
20.50
ATOM
856
CD1
LEU
260
32.904
−22.888
87.902
1.00
21.75
ATOM
857
CD2
LEU
260
31.485
−21.036
87.102
1.00
19.68
ATOM
858
C
LEU
260
30.306
−20.347
91.282
1.00
26.59
ATOM
859
O
LEU
260
30.823
−20.923
92.233
1.00
28.36
ATOM
860
N
LEU
261
29.076
−19.847
91.330
1.00
27.70
ATOM
861
CA
LEU
261
28.283
−19.905
92.557
1.00
28.07
ATOM
862
CB
LEU
261
27.611
−18.555
92.769
1.00
28.66
ATOM
863
CG
LEU
261
28.555
−17.374
92.533
1.00
28.66
ATOM
864
CD1
LEU
261
27.784
−16.071
92.672
1.00
28.33
ATOM
865
CD2
LEU
261
29.722
−17.433
93.517
1.00
28.00
ATOM
866
C
LEU
261
27.233
−21.004
92.632
1.00
28.30
ATOM
867
O
LEU
261
26.633
−21.362
91.635
1.00
27.56
ATOM
868
N
ASN
262
27.022
−21.538
93.831
1.00
30.19
ATOM
869
CA
ASN
262
26.026
−22.589
94.062
1.00
30.65
ATOM
870
CB
ASN
262
24.627
−21.988
93.972
1.00
30.68
ATOM
871
CG
ASN
262
24.446
−20.825
94.915
1.00
32.60
ATOM
872
OD1
ASN
262
25.131
−20.716
95.937
1.00
32.65
ATOM
873
ND2
ASN
262
23.506
−19.952
94.590
1.00
33.30
ATOM
874
C
ASN
262
26.107
−23.820
93.158
1.00
29.62
ATOM
875
O
ASN
262
25.084
−24.400
92.777
1.00
27.50
ATOM
876
N
GLY
263
27.328
−24.226
92.835
1.00
29.42
ATOM
877
CA
GLY
263
27.501
−25.384
91.983
1.00
30.33
ATOM
878
C
GLY
263
27.889
−26.635
92.734
1.00
29.97
ATOM
879
O
GLY
263
27.951
−26.638
93.954
1.00
30.00
ATOM
880
N
SER
264
28.148
−27.704
91.991
1.00
31.78
ATOM
881
CA
SER
264
28.540
−28.977
92.579
1.00
32.91
ATOM
882
CB
SER
264
28.367
−30.119
91.576
1.00
32.66
ATOM
883
OG
SER
264
27.014
−30.289
91.197
1.00
33.12
ATOM
884
C
SER
264
29.992
−28.926
92.992
1.00
33.65
ATOM
885
O
SER
264
30.813
−28.339
92.288
1.00
34.68
ATOM
886
N
LEU
265
30.301
−29.537
94.133
1.00
34.04
ATOM
887
CA
LEU
265
31.667
−29.588
94.627
1.00
34.32
ATOM
888
CB
LEU
265
31.689
−29.585
96.155
1.00
32.99
ATOM
889
CG
LEU
265
31.346
−28.271
96.859
1.00
33.66
ATOM
890
CD1
LEU
265
31.307
−28.477
98.352
1.00
34.03
ATOM
891
CD2
LEU
265
32.379
−27.219
96.520
1.00
34.44
ATOM
892
C
LEU
265
32.297
−30.869
94.098
1.00
35.56
ATOM
893
O
LEU
265
31.596
−31.751
93.607
1.00
34.43
ATOM
894
N
ALA
266
33.622
−30.951
94.176
1.00
38.30
ATOM
895
CA
ALA
266
34.352
−32.128
93.725
1.00
40.59
ATOM
896
CB
ALA
266
35.769
−31.751
93.302
1.00
38.89
ATOM
897
C
ALA
266
34.372
−33.070
94.920
1.00
43.62
ATOM
898
O
ALA
266
34.755
−32.677
96.026
1.00
44.02
ATOM
899
N
GLU
267
33.961
−34.314
94.691
1.00
46.39
ATOM
900
CA
GLU
267
33.868
−35.303
95.754
1.00
49.11
ATOM
901
CB
GLU
267
33.263
−36.593
95.198
1.00
51.72
ATOM
902
CG
GLU
267
32.103
−36.352
94.222
1.00
56.02
ATOM
903
CD
GLU
267
31.126
−37.527
94.130
1.00
57.75
ATOM
904
OE1
GLU
267
30.292
−37.680
95.053
1.00
58.56
ATOM
905
OE2
GLU
267
31.190
−38.294
93.139
1.00
58.03
ATOM
906
C
GLU
267
35.125
−35.625
96.554
1.00
49.70
ATOM
907
O
GLU
267
35.031
−35.933
97.736
1.00
50.00
ATOM
908
N
GLU
268
36.299
−35.552
95.944
1.00
51.35
ATOM
909
CA
GLU
268
37.510
−35.879
96.691
1.00
53.41
ATOM
910
CB
GLU
268
38.332
−36.923
95.940
1.00
55.13
ATOM
911
CG
GLU
268
37.589
−38.222
95.692
1.00
59.90
ATOM
912
CD
GLU
268
38.264
−39.115
94.650
1.00
61.80
ATOM
913
OE1
GLU
268
37.689
−40.179
94.332
1.00
62.83
ATOM
914
OE2
GLU
268
39.358
−38.756
94.154
1.00
62.29
ATOM
915
C
GLU
268
38.381
−34.672
96.964
1.00
53.78
ATOM
916
O
GLU
268
38.293
−34.046
98.023
1.00
54.54
ATOM
917
N
GLU
269
39.232
−34.355
96.000
1.00
53.53
ATOM
918
CA
GLU
269
40.139
−33.231
96.132
1.00
53.58
ATOM
919
CB
GLU
269
41.564
−33.689
95.841
1.00
55.20
ATOM
920
CG
GLU
269
41.923
−35.009
96.487
1.00
57.76
ATOM
921
CD
GLU
269
43.335
−35.450
96.151
1.00
59.84
ATOM
922
OE1
GLU
269
43.678
−36.621
96.416
1.00
59.87
ATOM
923
OE2
GLU
269
44.109
−34.623
95.626
1.00
62.07
ATOM
924
C
GLU
269
39.746
−32.126
95.162
1.00
52.41
ATOM
925
O
GLU
269
38.749
−32.252
94.452
1.00
53.19
ATOM
926
N
VAL
270
40.530
−31.049
95.138
1.00
50.34
ATOM
927
CA
VAL
270
40.269
−29.926
94.241
1.00
48.54
ATOM
928
CB
VAL
270
41.091
−28.663
94.633
1.00
47.63
ATOM
929
CG1
VAL
270
41.172
−27.707
93.467
1.00
45.74
ATOM
930
CG2
VAL
270
40.424
−27.950
95.806
1.00
47.67
ATOM
931
C
VAL
270
40.631
−30.337
92.823
1.00
47.45
ATOM
932
O
VAL
270
41.651
−30.994
92.606
1.00
47.66
ATOM
933
N
VAL
271
39.790
−29.948
91.864
1.00
45.27
ATOM
934
CA
VAL
271
40.012
−30.290
90.461
1.00
42.45
ATOM
935
CB
VAL
271
38.878
−31.202
89.925
1.00
41.54
ATOM
936
CG1
VAL
271
39.220
−31.677
88.530
1.00
39.33
ATOM
937
CG2
VAL
271
38.663
−32.380
90.857
1.00
40.44
ATOM
938
C
VAL
271
40.123
−29.071
89.535
1.00
40.87
ATOM
939
O
VAL
271
39.324
−28.132
89.623
1.00
41.07
ATOM
940
N
ILE
272
41.130
−29.096
88.662
1.00
37.99
ATOM
941
CA
ILE
272
41.342
−28.035
87.691
1.00
35.44
ATOM
942
CB
ILE
272
42.724
−27.352
87.867
1.00
32.95
ATOM
943
CG2
ILE
272
42.894
−26.892
89.302
1.00
30.53
ATOM
944
CG1
ILE
272
43.857
−28.308
87.528
1.00
30.50
ATOM
945
CD1
ILE
272
45.218
−27.694
87.759
1.00
28.89
ATOM
946
C
ILE
272
41.226
−28.705
86.329
1.00
36.01
ATOM
947
O
ILE
272
41.804
−29.760
86.104
1.00
36.26
ATOM
948
N
ARG
273
40.436
−28.100
85.444
1.00
36.70
ATOM
949
CA
ARG
273
40.173
−28.629
84.107
1.00
36.68
ATOM
950
CB
ARG
273
38.711
−29.077
83.996
1.00
34.08
ATOM
951
CG
ARG
273
38.209
−30.035
85.056
1.00
32.56
ATOM
952
CD
ARG
273
36.708
−30.273
84.871
1.00
32.51
ATOM
953
NE
ARG
273
36.253
−31.508
85.502
1.00
31.47
ATOM
954
CZ
ARG
273
36.149
−31.672
86.811
1.00
32.01
ATOM
955
NH1
ARG
273
36.458
−30.672
87.615
1.00
34.75
ATOM
956
NH2
ARG
273
35.771
−32.835
87.323
1.00
30.95
ATOM
957
C
ARG
273
40.409
−27.566
83.030
1.00
39.20
ATOM
958
O
ARG
273
40.272
−26.364
83.288
1.00
41.19
ATOM
959
N
SER
274
40.757
−28.013
81.823
1.00
40.06
ATOM
960
CA
SER
274
40.969
−27.114
80.691
1.00
40.76
ATOM
961
CB
SER
274
42.332
−26.436
80.763
1.00
36.80
ATOM
962
OG
SER
274
42.480
−25.540
79.681
1.00
32.87
ATOM
963
C
SER
274
40.867
−27.899
79.399
1.00
43.92
ATOM
964
O
SER
274
41.114
−29.100
79.372
1.00
45.39
ATOM
965
N
CYS
275
40.480
−27.230
78.325
1.00
47.15
ATOM
966
CA
CYS
275
40.377
−27.916
77.055
1.00
51.92
ATOM
967
C
CYS
275
41.737
−27.968
76.403
1.00
52.82
ATOM
968
O
CYS
275
41.890
−28.485
75.303
1.00
54.44
ATOM
969
CB
CYS
275
39.375
−27.207
76.154
1.00
55.95
ATOM
970
SG
CYS
275
37.681
−27.472
76.771
1.00
66.91
ATOM
971
N
ASN
276
42.730
−27.439
77.106
1.00
53.33
ATOM
972
CA
ASN
276
44.104
−27.397
76.624
1.00
52.97
ATOM
973
CB
ASN
276
44.161
−26.855
75.186
1.00
55.96
ATOM
974
CG
ASN
276
45.584
−26.683
74.685
1.00
61.01
ATOM
975
OD1
ASN
276
46.331
−25.861
75.210
1.00
63.58
ATOM
976
ND2
ASN
276
45.980
−27.485
73.701
1.00
64.98
ATOM
977
C
ASN
276
44.864
−26.475
77.571
1.00
51.50
ATOM
978
O
ASN
276
44.876
−25.251
77.398
1.00
50.11
ATOM
979
N
PHE
277
45.483
−27.074
78.584
1.00
49.28
ATOM
980
CA
PHE
277
46.235
−26.309
79.570
1.00
47.85
ATOM
981
CB
PHE
277
46.763
−27.231
80.675
1.00
46.32
ATOM
982
CG
PHE
277
45.689
−27.794
81.567
1.00
44.69
ATOM
983
CD1
PHE
277
45.136
−29.050
81.321
1.00
43.74
ATOM
984
CD2
PHE
277
45.235
−27.070
82.667
1.00
43.64
ATOM
985
CE1
PHE
277
44.149
−29.577
82.163
1.00
41.58
ATOM
986
CE2
PHE
277
44.249
−27.590
83.511
1.00
42.49
ATOM
987
CZ
PHE
277
43.707
−28.848
83.258
1.00
40.91
ATOM
988
C
PHE
277
47.397
−25.526
78.959
1.00
47.27
ATOM
989
O
PHE
277
47.758
−24.456
79.451
1.00
46.87
ATOM
990
N
THR
278
47.972
−26.069
77.890
1.00
47.46
ATOM
991
CA
THR
278
49.103
−25.462
77.189
1.00
48.47
ATOM
992
CB
THR
278
49.612
−26.414
76.092
1.00
48.42
ATOM
993
OG1
THR
278
50.438
−27.415
76.691
1.00
48.33
ATOM
994
CG2
THR
278
50.410
−25.659
75.038
1.00
49.75
ATOM
995
C
THR
278
48.784
−24.103
76.562
1.00
48.99
ATOM
996
O
THR
278
49.596
−23.168
76.609
1.00
48.80
ATOM
997
N
ASP
279
47.600
−24.021
75.964
1.00
48.66
ATOM
998
CA
ASP
279
47.094
−22.816
75.315
1.00
48.23
ATOM
999
CB
ASP
279
45.819
−23.178
74.547
1.00
50.23
ATOM
1000
CG
ASP
279
45.261
−22.025
73.742
1.00
51.68
ATOM
1001
OD1
ASP
279
44.294
−22.275
72.986
1.00
51.77
ATOM
1002
OD2
ASP
279
45.778
−20.890
73.870
1.00
51.55
ATOM
1003
C
ASP
279
46.792
−21.801
76.414
1.00
47.12
ATOM
1004
O
ASP
279
45.827
−21.958
77.168
1.00
47.67
ATOM
1005
N
ASN
280
47.609
−20.758
76.507
1.00
43.96
ATOM
1006
CA
ASN
280
47.410
−19.775
77.559
1.00
41.43
ATOM
1007
CB
ASN
280
48.671
−18.910
77.722
1.00
39.74
ATOM
1008
CG
ASN
280
49.007
−18.101
76.485
1.00
36.68
ATOM
1009
OD1
ASN
280
48.755
−18.525
75.364
1.00
36.56
ATOM
1010
ND2
ASN
280
49.604
−16.931
76.692
1.00
33.53
ATOM
1011
C
ASN
280
46.174
−18.916
77.364
1.00
41.24
ATOM
1012
O
ASN
280
45.970
−17.927
78.058
1.00
40.99
ATOM
1013
N
ALA
281
45.321
−19.315
76.434
1.00
41.19
ATOM
1014
CA
ALA
281
44.117
−18.547
76.192
1.00
40.89
ATOM
1015
CB
ALA
281
44.119
−18.045
74.777
1.00
42.27
ATOM
1016
C
ALA
281
42.859
−19.356
76.463
1.00
40.32
ATOM
1017
O
ALA
281
41.764
−18.949
76.090
1.00
41.07
ATOM
1018
N
LYS
282
43.012
−20.500
77.115
1.00
39.16
ATOM
1019
CA
LYS
282
41.864
−21.334
77.423
1.00
38.60
ATOM
1020
CB
LYS
282
42.116
−22.773
76.970
1.00
39.99
ATOM
1021
CG
LYS
282
41.897
−22.990
75.479
1.00
41.46
ATOM
1022
CD
LYS
282
40.523
−22.473
75.048
1.00
43.09
ATOM
1023
CE
LYS
282
40.172
−22.875
73.625
1.00
41.82
ATOM
1024
NZ
LYS
282
39.986
−24.349
73.519
1.00
42.86
ATOM
1025
C
LYS
282
41.488
−21.310
78.897
1.00
37.93
ATOM
1026
O
LYS
282
42.336
−21.477
79.777
1.00
38.22
ATOM
1027
N
THR
283
40.200
−21.110
79.149
1.00
36.68
ATOM
1028
CA
THR
283
39.648
−21.049
80.494
1.00
35.31
ATOM
1029
CB
THR
283
38.117
−20.944
80.447
1.00
34.66
ATOM
1030
OG1
THR
283
37.745
−19.702
79.850
1.00
37.62
ATOM
1031
CG2
THR
283
37.523
−21.018
81.833
1.00
34.32
ATOM
1032
C
THR
283
39.982
−22.263
81.340
1.00
35.03
ATOM
1033
O
THR
283
39.808
−23.396
80.896
1.00
35.94
ATOM
1034
N
ILE
284
40.461
−22.026
82.558
1.00
33.55
ATOM
1035
CA
ILE
284
40.750
−23.115
83.481
1.00
32.06
ATOM
1036
CB
ILE
284
42.087
−22.926
84.220
1.00
29.94
ATOM
1037
CG2
ILE
284
42.264
−24.025
85.253
1.00
25.00
ATOM
1038
CG1
ILE
284
43.234
−22.964
83.225
1.00
28.55
ATOM
1039
CD1
ILE
284
44.563
−22.787
83.859
1.00
28.55
ATOM
1040
C
ILE
284
39.609
−23.124
84.502
1.00
33.37
ATOM
1041
O
ILE
284
39.398
−22.149
85.237
1.00
32.79
ATOM
1042
N
ILE
285
38.867
−24.227
84.516
1.00
33.28
ATOM
1043
CA
ILE
285
37.740
−24.413
85.412
1.00
32.89
ATOM
1044
CB
ILE
285
36.657
−25.259
84.734
1.00
31.95
ATOM
1045
CG2
ILE
285
35.537
−25.555
85.697
1.00
32.46
ATOM
1046
CG1
ILE
285
36.113
−24.517
83.527
1.00
32.81
ATOM
1047
CD1
ILE
285
34.981
−25.242
82.844
1.00
35.28
ATOM
1048
C
ILE
285
38.158
−25.122
86.695
1.00
34.13
ATOM
1049
O
ILE
285
38.440
−26.313
86.690
1.00
35.08
ATOM
1050
N
VAL
286
38.206
−24.398
87.799
1.00
34.62
ATOM
1051
CA
VAL
286
38.566
−25.024
89.056
1.00
34.98
ATOM
1052
CB
VAL
286
39.403
−24.051
89.931
1.00
34.50
ATOM
1053
CG1
VAL
286
39.593
−24.600
91.335
1.00
31.43
ATOM
1054
CG2
VAL
286
40.743
−23.843
89.292
1.00
34.26
ATOM
1055
C
VAL
286
37.276
−25.413
89.788
1.00
36.26
ATOM
1056
O
VAL
286
36.276
−24.683
89.736
1.00
36.24
ATOM
1057
N
GLN
287
37.290
−26.581
90.425
1.00
35.78
ATOM
1058
CA
GLN
287
36.151
−27.041
91.210
1.00
36.32
ATOM
1059
CB
GLN
287
35.441
−28.214
90.547
1.00
35.89
ATOM
1060
CG
GLN
287
34.369
−28.830
91.444
1.00
35.81
ATOM
1061
CD
GLN
287
33.732
−30.067
90.834
1.00
35.51
ATOM
1062
OE1
GLN
287
34.394
−30.838
90.141
1.00
34.61
ATOM
1063
NE2
GLN
287
32.446
−30.269
91.102
1.00
34.71
ATOM
1064
C
GLN
287
36.673
−27.444
92.595
1.00
36.79
ATOM
1065
O
GLN
287
37.691
−28.131
92.728
1.00
35.75
ATOM
1066
N
LEU
288
35.955
−27.011
93.623
1.00
37.06
ATOM
1067
CA
LEU
288
36.357
−27.248
94.996
1.00
37.17
ATOM
1068
CB
LEU
288
36.146
−25.962
95.805
1.00
34.97
ATOM
1069
CG
LEU
288
36.614
−24.630
95.206
1.00
32.83
ATOM
1070
CD1
LEU
288
35.969
−23.494
95.955
1.00
31.53
ATOM
1071
CD2
LEU
288
38.120
−24.514
95.268
1.00
31.88
ATOM
1072
C
LEU
288
35.653
−28.405
95.707
1.00
38.46
ATOM
1073
O
LEU
288
34.553
−28.817
95.334
1.00
38.22
ATOM
1074
N
ASN
289
36.322
−28.898
96.748
1.00
39.95
ATOM
1075
CA
ASN
289
35.855
−29.984
97.605
1.00
40.45
ATOM
1076
CB
ASN
289
37.057
−30.772
98.117
1.00
40.55
ATOM
1077
CG
ASN
289
38.027
−29.893
98.867
1.00
42.68
ATOM
1078
OD1
ASN
289
38.080
−28.692
98.600
1.00
43.84
ATOM
1079
ND2
ASN
289
38.797
−30.451
99.798
1.00
45.54
ATOM
1080
C
ASN
289
35.136
−29.342
98.793
1.00
40.56
ATOM
1081
O
ASN
289
34.426
−30.011
99.534
1.00
41.39
ATOM
1082
N
THR
290
35.334
−28.037
98.971
1.00
40.82
ATOM
1083
CA
THR
290
34.716
−27.293
100.075
1.00
39.80
ATOM
1084
CB
THR
290
35.738
−26.968
101.168
1.00
40.22
ATOM
1085
OG1
THR
290
36.425
−28.160
101.564
1.00
40.45
ATOM
1086
CG2
THR
290
35.038
−26.345
102.361
1.00
40.96
ATOM
1087
C
THR
290
34.141
−25.953
99.630
1.00
38.45
ATOM
1088
O
THR
290
34.790
−25.211
98.898
1.00
38.51
ATOM
1089
N
SER
291
32.941
−25.626
100.093
1.00
37.41
ATOM
1090
CA
SER
291
32.334
−24.349
99.735
1.00
36.56
ATOM
1091
CB
SER
291
30.834
−24.367
100.019
1.00
37.11
ATOM
1092
OG
SER
291
30.126
−25.014
98.978
1.00
40.14
ATOM
1093
C
SER
291
32.965
−23.232
100.537
1.00
35.66
ATOM
1094
O
SER
291
33.504
−23.480
101.604
1.00
36.84
ATOM
1095
N
VAL
292
32.919
−22.012
100.002
1.00
35.35
ATOM
1096
CA
VAL
292
33.432
−20.806
100.682
1.00
34.01
ATOM
1097
CB
VAL
292
34.734
−20.239
100.018
1.00
32.71
ATOM
1098
CG1
VAL
292
35.059
−18.859
100.597
1.00
27.63
ATOM
1099
CG2
VAL
292
35.907
−21.193
100.257
1.00
29.57
ATOM
1100
C
VAL
292
32.306
−19.784
100.537
1.00
33.54
ATOM
1101
O
VAL
292
31.983
−19.374
99.426
1.00
33.35
ATOM
1102
N
GLU
293
31.691
−19.379
101.639
1.00
33.37
ATOM
1103
CA
GLU
293
30.580
−18.440
101.519
1.00
34.15
ATOM
1104
CB
GLU
293
29.834
−18.262
102.846
1.00
37.09
ATOM
1105
CG
GLU
293
29.612
−19.536
103.649
1.00
44.11
ATOM
1106
CD
GLU
293
30.893
−20.000
104.321
1.00
50.19
ATOM
1107
OE1
GLU
293
31.452
−19.216
105.135
1.00
53.93
ATOM
1108
OE2
GLU
293
31.350
−21.131
104.033
1.00
51.72
ATOM
1109
C
GLU
293
31.013
−17.077
101.036
1.00
32.44
ATOM
1110
O
GLU
293
32.131
−16.632
101.270
1.00
32.48
ATOM
1111
N
ILE
294
30.112
−16.419
100.334
1.00
31.24
ATOM
1112
CA
ILE
294
30.371
−15.080
99.858
1.00
31.02
ATOM
1113
CB
ILE
294
30.909
−15.060
98.407
1.00
28.57
ATOM
1114
CG2
ILE
294
29.896
−15.631
97.459
1.00
28.94
ATOM
1115
CG1
ILE
294
31.228
−13.627
97.999
1.00
26.61
ATOM
1116
CD1
ILE
294
31.771
−13.513
96.622
1.00
26.35
ATOM
1117
C
ILE
294
29.018
−14.391
99.953
1.00
32.34
ATOM
1118
O
ILE
294
28.050
−14.785
99.293
1.00
31.74
ATOM
1119
N
ASN
295
28.943
−13.381
100.811
1.00
33.69
ATOM
1120
CA
ASN
295
27.694
−12.666
101.002
1.00
36.46
ATOM
1121
CB
ASN
295
27.305
−12.678
102.484
1.00
36.40
ATOM
1122
CG
ASN
295
27.390
−14.059
103.099
1.00
36.18
ATOM
1123
OD1
ASN
295
26.783
−15.025
102.619
1.00
32.60
ATOM
1124
ND2
ASN
295
28.148
−14.155
104.180
1.00
37.07
ATOM
1125
C
ASN
295
27.801
−11.230
100.513
1.00
37.74
ATOM
1126
O
ASN
295
28.729
−10.512
100.889
1.00
37.01
ATOM
1127
N
CYS
296
26.852
−10.822
99.672
1.00
39.54
ATOM
1128
CA
CYS
296
26.853
−9.467
99.142
1.00
40.74
ATOM
1129
C
CYS
296
25.546
−8.761
99.438
1.00
39.17
ATOM
1130
O
CYS
296
24.554
−9.388
99.804
1.00
37.88
ATOM
1131
CB
CYS
296
27.051
−9.468
97.637
1.00
43.38
ATOM
1132
SG
CYS
296
28.393
−10.504
96.984
1.00
50.13
ATOM
1133
N
THR
297
25.548
−7.450
99.241
1.00
38.11
ATOM
1134
CA
THR
297
24.368
−6.654
99.498
1.00
38.11
ATOM
1135
CB
THR
297
24.326
−6.200
100.953
1.00
39.36
ATOM
1136
OG1
THR
297
23.087
−5.522
101.209
1.00
40.89
ATOM
1137
CG2
THR
297
25.500
−5.261
101.241
1.00
37.42
ATOM
1138
C
THR
297
24.348
−5.412
98.629
1.00
37.88
ATOM
1139
O
THR
297
25.400
−4.820
98.356
1.00
37.71
ATOM
1140
N
GLY
298
23.144
−5.011
98.218
1.00
36.98
ATOM
1141
CA
GLY
298
22.990
−3.829
97.389
1.00
36.14
ATOM
1142
C
GLY
298
23.541
−2.583
98.058
1.00
35.80
ATOM
1143
O
GLY
298
23.479
−1.486
97.499
1.00
35.86
ATOM
1144
N
ALA
299
24.079
−2.752
99.262
1.00
35.67
ATOM
1145
CA
ALA
299
24.648
−1.644
100.018
1.00
34.99
ATOM
1146
CB
ALA
299
24.757
−2.001
101.506
1.00
35.85
ATOM
1147
C
ALA
299
26.014
−1.346
99.450
1.00
34.21
ATOM
1148
O
ALA
299
26.628
−0.354
99.809
1.00
34.18
ATOM
1149
N
GLY
329
26.503
−2.232
98.591
1.00
34.17
ATOM
1150
CA
GLY
329
27.785
−1.988
97.965
1.00
35.52
ATOM
1151
C
GLY
329
28.940
−2.931
98.199
1.00
36.98
ATOM
1152
O
GLY
329
30.059
−2.611
97.805
1.00
37.25
ATOM
1153
N
HIS
330
28.709
−4.086
98.817
1.00
39.63
ATOM
1154
CA
HIS
330
29.827
−5.002
99.058
1.00
40.25
ATOM
1155
CB
HIS
330
30.600
−4.559
100.305
1.00
39.30
ATOM
1156
CG
HIS
330
29.818
−4.666
101.578
1.00
40.80
ATOM
1157
CD2
HIS
330
30.171
−5.105
102.807
1.00
42.00
ATOM
1158
ND1
HIS
330
28.516
−4.227
101.693
1.00
41.71
ATOM
1159
CE1
HIS
330
28.105
−4.386
102.936
1.00
41.88
ATOM
1160
NE2
HIS
330
29.090
−4.918
103.636
1.00
42.53
ATOM
1161
C
HIS
330
29.536
−6.504
99.162
1.00
40.37
ATOM
1162
O
HIS
330
28.388
−6.961
99.125
1.00
38.87
ATOM
1163
N
CYS
331
30.630
−7.255
99.255
1.00
41.78
ATOM
1164
CA
CYS
331
30.620
−8.702
99.394
1.00
42.53
ATOM
1165
C
CYS
331
31.656
−9.068
100.444
1.00
41.74
ATOM
1166
O
CYS
331
32.783
−8.569
100.418
1.00
40.56
ATOM
1167
CB
CYS
331
31.022
−9.387
98.105
1.00
44.95
ATOM
1168
SG
CYS
331
29.923
−9.199
96.679
1.00
48.68
ATOM
1169
N
ASN
332
31.273
−9.945
101.359
1.00
40.38
ATOM
1170
CA
ASN
332
32.189
−10.364
102.386
1.00
40.12
ATOM
1171
CB
ASN
332
31.556
−10.224
103.766
1.00
42.37
ATOM
1172
CG
ASN
332
31.322
−8.777
104.151
1.00
44.33
ATOM
1173
OD1
ASN
332
32.169
−7.911
103.909
1.00
44.82
ATOM
1174
ND2
ASN
332
30.175
−8.509
104.768
1.00
44.71
ATOM
1175
C
ASN
332
32.586
−11.795
102.141
1.00
39.72
ATOM
1176
O
ASN
332
31.793
−12.607
101.661
1.00
38.64
ATOM
1177
N
ILE
333
33.834
−12.088
102.472
1.00
40.00
ATOM
1178
CA
ILE
333
34.387
−13.416
102.317
1.00
40.51
ATOM
1179
CB
ILE
333
35.109
−13.544
100.985
1.00
40.85
ATOM
1180
CG2
ILE
333
35.936
−14.821
100.957
1.00
42.34
ATOM
1181
CG1
ILE
333
34.089
−13.520
99.855
1.00
40.11
ATOM
1182
CD1
ILE
333
34.709
−13.314
98.515
1.00
41.51
ATOM
1183
C
ILE
333
35.381
−13.647
103.432
1.00
40.36
ATOM
1184
O
ILE
333
36.201
−12.780
103.723
1.00
40.87
ATOM
1185
N
ALA
334
35.299
−14.812
104.060
1.00
39.60
ATOM
1186
CA
ALA
334
36.204
−15.156
105.147
1.00
38.54
ATOM
1187
CB
ALA
334
35.762
−16.471
105.757
1.00
41.22
ATOM
1189
C
ALA
334
37.614
−15.275
104.590
1.00
36.87
ATOM
1190
O
ALA
334
37.883
−16.097
103.715
1.00
33.76
ATOM
1191
N
ARG
335
38.510
−14.444
105.102
1.00
36.58
ATOM
1192
CA
ARG
335
39.883
−14.434
104.628
1.00
37.37
ATOM
1193
CB
ARG
335
40.669
−13.333
105.326
1.00
36.39
ATOM
1194
CG
ARG
335
42.094
−13.213
104.847
1.00
38.55
ATOM
1195
CD
ARG
335
42.801
−12.047
105.516
1.00
42.33
ATOM
1196
NE
ARG
335
42.268
−10.762
105.079
1.00
44.44
ATOM
1197
CZ
ARG
335
42.375
−10.305
103.837
1.00
45.53
ATOM
1198
NH1
ARG
335
42.999
−11.034
102.924
1.00
46.03
ATOM
1199
NH2
ARG
335
41.856
−9.127
103.509
1.00
46.38
ATOM
1200
C
ARG
335
40.558
−15.774
104.855
1.00
38.44
ATOM
1201
O
ARG
335
41.318
−16.259
104.012
1.00
39.73
ATOM
1202
N
ALA
336
40.276
−16.375
106.000
1.00
38.31
ATOM
1203
CA
ALA
336
40.849
−17.664
106.347
1.00
38.08
ATOM
1204
CB
ALA
336
40.436
−18.025
107.750
1.00
38.47
ATOM
1205
C
ALA
336
40.393
−18.754
105.371
1.00
38.68
ATOM
1206
O
ALA
336
41.214
−19.420
104.728
1.00
37.19
ATOM
1207
N
LYS
337
39.078
−18.934
105.271
1.00
39.27
ATOM
1208
CA
LYS
337
38.523
−19.932
104.376
1.00
39.56
ATOM
1209
CB
LYS
337
37.003
−19.839
104.339
1.00
40.15
ATOM
1210
CG
LYS
337
36.316
−20.161
105.642
1.00
42.29
ATOM
1211
CD
LYS
337
34.875
−20.564
105.373
1.00
44.78
ATOM
1212
CE
LYS
337
34.130
−20.917
106.647
1.00
46.19
ATOM
1213
NZ
LYS
337
32.829
−21.580
106.331
1.00
47.33
ATOM
1214
C
LYS
337
39.066
−19.744
102.974
1.00
39.65
ATOM
1215
O
LYS
337
39.464
−20.699
102.329
1.00
39.54
ATOM
1216
N
TRP
338
39.086
−18.506
102.501
1.00
41.16
ATOM
1217
CA
TRP
338
39.585
−18.252
101.159
1.00
43.17
ATOM
1218
CB
TRP
338
39.319
−16.817
100.725
1.00
40.60
ATOM
1219
CG
TRP
338
39.685
−16.593
99.290
1.00
37.38
ATOM
1220
CD2
TRP
338
38.950
−17.042
98.154
1.00
36.44
ATOM
1221
CE2
TRP
338
39.646
−16.608
97.004
1.00
36.35
ATOM
1222
CE3
TRP
338
37.765
−17.774
97.993
1.00
35.17
ATOM
1223
CD1
TRP
338
40.777
−15.928
98.803
1.00
36.91
ATOM
1224
NE1
TRP
338
40.761
−15.930
97.427
1.00
35.85
ATOM
1225
CZ2
TRP
338
39.194
−16.878
95.714
1.00
36.13
ATOM
1226
CZ3
TRP
338
37.316
−18.044
96.712
1.00
34.19
ATOM
1227
CH2
TRP
338
38.028
−17.596
95.588
1.00
35.36
ATOM
1228
C
TRP
338
41.069
−18.515
101.032
1.00
46.01
ATOM
1229
O
TRP
338
41.523
−19.094
100.045
1.00
46.74
ATOM
1230
N
ASN
339
41.836
−18.083
102.020
1.00
48.56
ATOM
1231
CA
ASN
339
43.260
−18.298
101.949
1.00
51.16
ATOM
1232
CB
ASN
339
43.957
−17.688
103.143
1.00
56.16
ATOM
1233
CG
ASN
339
45.435
−17.890
103.080
1.00
63.56
ATOM
1234
OD1
ASN
339
46.073
−17.445
102.132
1.00
64.19
ATOM
1235
ND2
ASN
339
45.995
−18.566
104.079
1.00
71.86
ATOM
1236
C
ASN
339
43.605
−19.777
101.860
1.00
50.86
ATOM
1237
O
ASN
339
44.597
−20.144
101.242
1.00
50.87
ATOM
1238
N
ASN
340
42.800
−20.634
102.478
1.00
50.99
ATOM
1239
CA
ASN
340
43.071
−22.067
102.407
1.00
51.70
ATOM
1240
CB
ASN
340
42.192
−22.862
103.371
1.00
54.49
ATOM
1241
CG
ASN
340
42.634
−22.724
104.808
1.00
58.41
ATOM
1242
OD1
ASN
340
43.787
−23.014
105.151
1.00
60.24
ATOM
1243
ND2
ASN
340
41.719
−22.288
105.666
1.00
60.46
ATOM
1244
C
ASN
340
42.781
−22.540
101.004
1.00
50.85
ATOM
1245
O
ASN
340
43.537
−23.331
100.433
1.00
51.84
ATOM
1246
N
THR
341
41.669
−22.058
100.456
1.00
48.01
ATOM
1247
CA
THR
341
41.269
−22.434
99.116
1.00
45.14
ATOM
1248
CB
THR
341
39.989
−21.678
98.686
1.00
44.64
ATOM
1249
OG1
THR
341
38.964
−21.883
99.667
1.00
42.76
ATOM
1250
CG2
THR
341
39.488
−22.189
97.334
1.00
42.30
ATOM
1251
C
THR
341
42.416
−22.124
98.163
1.00
44.38
ATOM
1252
O
THR
341
42.821
−22.977
97.377
1.00
42.42
ATOM
1253
N
LEU
342
42.959
−20.911
98.249
1.00
44.37
ATOM
1254
CA
LEU
342
44.061
−20.531
97.373
1.00
44.41
ATOM
1255
CB
LEU
342
44.506
−19.087
97.635
1.00
43.85
ATOM
1256
CG
LEU
342
43.507
−17.950
97.335
1.00
44.37
ATOM
1257
CD1
LEU
342
44.162
−16.606
97.623
1.00
43.63
ATOM
1258
CD2
LEU
342
43.050
−17.996
95.894
1.00
43.05
ATOM
1259
C
LEU
342
45.245
−21.489
97.514
1.00
44.72
ATOM
1260
O
LEU
342
45.858
−21.851
96.515
1.00
45.32
ATOM
1261
N
LYS
343
45.567
−21.917
98.735
1.00
44.30
ATOM
1262
CA
LYS
343
46.678
−22.854
98.921
1.00
43.59
ATOM
1263
CB
LYS
343
46.928
−23.141
100.406
1.00
44.40
ATOM
1264
CG
LYS
343
48.240
−23.898
100.658
1.00
46.15
ATOM
1265
CD
LYS
343
48.413
−24.323
102.114
1.00
49.16
ATOM
1266
CE
LYS
343
48.578
−23.136
103.080
1.00
52.93
ATOM
1267
NZ
LYS
343
49.893
−22.400
103.011
1.00
53.31
ATOM
1268
C
LYS
343
46.388
−24.173
98.206
1.00
42.93
ATOM
1269
O
LYS
343
47.242
−24.709
97.493
1.00
42.92
ATOM
1270
N
GLN
344
45.179
−24.693
98.396
1.00
42.56
ATOM
1271
CA
GLN
344
44.778
−25.957
97.777
1.00
42.99
ATOM
1272
CB
GLN
344
43.385
−26.373
98.241
1.00
41.89
ATOM
1273
CG
GLN
344
43.168
−26.344
99.725
1.00
42.51
ATOM
1274
CD
GLN
344
41.735
−26.664
100.081
1.00
43.88
ATOM
1275
OE1
GLN
344
41.243
−27.736
99.755
1.00
45.09
ATOM
1276
NE2
GLN
344
41.052
−25.728
100.744
1.00
44.66
ATOM
1277
C
GLN
344
44.762
−25.908
96.254
1.00
43.37
ATOM
1278
O
GLN
344
44.870
−26.952
95.612
1.00
44.99
ATOM
1279
N
ILE
345
44.602
−24.714
95.679
1.00
43.39
ATOM
1280
CA
ILE
345
44.559
−24.567
94.218
1.00
42.52
ATOM
1281
CB
ILE
345
43.705
−23.359
93.765
1.00
40.62
ATOM
1282
CG2
ILE
345
43.479
−23.434
92.280
1.00
39.28
ATOM
1283
CG1
ILE
345
42.332
−23.377
94.419
1.00
40.32
ATOM
1284
CD1
ILE
345
41.517
−22.134
94.104
1.00
40.02
ATOM
1285
C
ILE
345
45.946
−24.394
93.611
1.00
43.06
ATOM
1286
O
ILE
345
46.281
−25.050
92.626
1.00
42.31
ATOM
1287
N
ALA
346
46.745
−23.496
94.184
1.00
44.37
ATOM
1288
CA
ALA
346
48.097
−23.273
93.683
1.00
45.42
ATOM
1289
CB
ALA
346
48.836
−22.275
94.556
1.00
43.26
ATOM
1290
C
ALA
346
48.771
−24.630
93.743
1.00
46.84
ATOM
1291
O
ALA
346
49.582
−24.981
92.886
1.00
47.39
ATOM
1292
N
SER
347
48.408
−25.396
94.765
1.00
47.70
ATOM
1293
CA
SER
347
48.950
−26.722
94.934
1.00
49.50
ATOM
1294
CB
SER
347
48.337
−27.376
96.160
1.00
51.28
ATOM
1295
OG
SER
347
48.850
−28.685
96.317
1.00
56.57
ATOM
1296
C
SER
347
48.662
−27.558
93.683
1.00
49.94
ATOM
1297
O
SER
347
49.586
−28.029
93.030
1.00
50.34
ATOM
1298
N
LYS
348
47.382
−27.728
93.351
1.00
50.78
ATOM
1299
CA
LYS
348
46.962
−28.494
92.170
1.00
51.63
ATOM
1300
CB
LYS
348
45.432
−28.577
92.098
1.00
51.50
ATOM
1301
CG
LYS
348
44.791
−29.584
93.032
1.00
51.75
ATOM
1302
CD
LYS
348
45.064
−30.988
92.556
1.00
50.85
ATOM
1303
CE
LYS
348
44.542
−32.004
93.543
1.00
50.69
ATOM
1304
NZ
LYS
348
44.944
−33.375
93.137
1.00
50.94
ATOM
1305
C
LYS
348
47.463
−27.869
90.869
1.00
52.28
ATOM
1306
O
LYS
348
47.585
−28.535
89.840
1.00
52.16
ATOM
1307
N
LEU
349
47.738
−26.579
90.908
1.00
53.08
ATOM
1308
CA
LEU
349
48.203
−25.921
89.713
1.00
55.10
ATOM
1309
CB
LEU
349
48.002
−24.402
89.824
1.00
53.88
ATOM
1310
CG
LEU
349
46.572
−23.855
89.720
1.00
50.78
ATOM
1311
CD1
LEU
349
46.600
−22.369
89.985
1.00
49.11
ATOM
1312
CD2
LEU
349
45.977
−24.134
88.345
1.00
47.99
ATOM
1313
C
LEU
349
49.655
−26.259
89.402
1.00
57.08
ATOM
1314
O
LEU
349
49.959
−26.620
88.270
1.00
57.54
ATOM
1315
N
ARG
350
50.555
−26.159
90.383
1.00
59.82
ATOM
1316
CA
ARG
350
51.961
−26.476
90.114
1.00
63.18
ATOM
1317
CB
ARG
350
52.866
−26.042
91.266
1.00
64.31
ATOM
1318
CG
ARG
350
52.410
−26.471
92.624
1.00
68.34
ATOM
1319
CD
ARG
350
53.595
−26.540
93.563
1.00
72.56
ATOM
1320
NE
ARG
350
54.525
−25.427
93.375
1.00
76.31
ATOM
1321
CZ
ARG
350
55.714
−25.343
93.974
1.00
78.63
ATOM
1322
NH1
ARG
350
56.113
−26.308
94.798
1.00
78.98
ATOM
1323
NH2
ARG
350
56.511
−24.301
93.751
1.00
79.29
ATOM
1324
C
ARG
350
52.125
−27.968
89.851
1.00
64.33
ATOM
1325
O
ARG
350
53.102
−28.405
89.234
1.00
65.71
ATOM
1326
N
GLU
351
51.148
−28.741
90.312
1.00
64.55
ATOM
1327
CA
GLU
351
51.126
−30.180
90.112
1.00
63.62
ATOM
1328
CB
GLU
351
49.963
−30.778
90.898
1.00
66.10
ATOM
1329
CG
GLU
351
49.896
−32.290
90.914
1.00
70.44
ATOM
1330
CD
GLU
351
48.652
−32.811
91.628
1.00
72.67
ATOM
1331
OE1
GLU
351
47.536
−32.631
91.090
1.00
74.72
ATOM
1332
OE2
GLU
351
48.787
−33.397
92.726
1.00
73.74
ATOM
1333
C
GLU
351
50.941
−30.456
88.615
1.00
61.98
ATOM
1334
O
GLU
351
51.096
−31.588
88.162
1.00
61.55
ATOM
1335
N
GLN
352
50.602
−29.409
87.861
1.00
60.65
ATOM
1336
CA
GLN
352
50.397
−29.505
86.415
1.00
59.13
ATOM
1337
CB
GLN
352
48.942
−29.191
86.053
1.00
56.49
ATOM
1338
CG
GLN
352
48.699
−29.115
84.545
1.00
53.84
ATOM
1339
CD
GLN
352
47.501
−29.931
84.092
1.00
52.61
ATOM
1340
OE1
GLN
352
47.280
−30.122
82.895
1.00
49.99
ATOM
1341
NE2
GLN
352
46.722
−30.416
85.048
1.00
52.71
ATOM
1342
C
GLN
352
51.320
−28.619
85.563
1.00
59.46
ATOM
1343
O
GLN
352
51.494
−28.873
84.375
1.00
58.99
ATOM
1344
N
PHE
353
51.908
−27.585
86.152
1.00
60.32
ATOM
1345
CA
PHE
353
52.796
−26.714
85.390
1.00
62.07
ATOM
1346
CB
PHE
353
52.262
−25.277
85.366
1.00
61.62
ATOM
1347
CG
PHE
353
50.957
−25.129
84.641
1.00
61.43
ATOM
1348
CD1
PHE
353
49.752
−25.258
85.316
1.00
61.91
ATOM
1349
CD2
PHE
353
50.930
−24.905
83.268
1.00
62.10
ATOM
1350
CE1
PHE
353
48.532
−25.168
84.633
1.00
62.04
ATOM
1351
CE2
PHE
353
49.717
−24.815
82.576
1.00
61.69
ATOM
1352
CZ
PHE
353
48.516
−24.948
83.261
1.00
61.58
ATOM
1353
C
PHE
353
54.229
−26.713
85.915
1.00
64.18
ATOM
1354
O
PHE
353
55.046
−25.880
85.511
1.00
65.29
ATOM
1355
N
GLY
354
54.540
−27.642
86.812
1.00
64.51
ATOM
1356
CA
GLY
354
55.888
−27.697
87.340
1.00
65.83
ATOM
1357
C
GLY
354
55.948
−27.501
88.838
1.00
67.15
ATOM
1358
O
GLY
354
55.746
−26.395
89.346
1.00
67.01
ATOM
1359
N
ASN
355
56.237
−28.589
89.544
1.00
67.83
ATOM
1360
CA
ASN
355
56.329
−28.576
90.994
1.00
68.59
ATOM
1361
CB
ASN
355
56.573
−29.995
91.513
1.00
70.55
ATOM
1362
CG
ASN
355
55.301
−30.841
91.533
1.00
72.72
ATOM
1363
OD1
ASN
355
55.353
−32.048
91.776
1.00
74.24
ATOM
1364
ND2
ASN
355
54.155
−30.208
91.290
1.00
72.93
ATOM
1365
C
ASN
355
57.413
−27.644
91.509
1.00
68.43
ATOM
1366
O
ASN
355
57.574
−27.480
92.716
1.00
69.01
ATOM
1367
N
ASN
356
58.155
−27.032
90.597
1.00
67.89
ATOM
1368
CA
ASN
356
59.214
−26.114
90.988
1.00
67.81
ATOM
1369
CB
ASN
356
60.495
−26.427
90.209
1.00
68.67
ATOM
1370
CG
ASN
356
61.021
−27.836
90.475
1.00
68.82
ATOM
1371
OD1
ASN
356
62.067
−28.223
89.956
1.00
68.37
ATOM
1372
ND2
ASN
356
60.294
−28.605
91.282
1.00
69.10
ATOM
1373
C
ASN
356
58.756
−24.690
90.698
1.00
67.61
ATOM
1374
O
ASN
356
59.399
−23.719
91.109
1.00
68.06
ATOM
1375
N
LYS
357
57.632
−24.588
89.989
1.00
66.72
ATOM
1376
CA
LYS
357
57.028
−23.308
89.603
1.00
64.44
ATOM
1377
CB
LYS
357
55.979
−23.528
88.503
1.00
65.55
ATOM
1378
CG
LYS
357
56.524
−23.915
87.138
1.00
66.86
ATOM
1379
CD
LYS
357
57.287
−22.758
86.511
1.00
68.57
ATOM
1380
CE
LYS
357
57.563
−22.990
85.033
1.00
69.07
ATOM
1381
NZ
LYS
357
56.297
−23.017
84.250
1.00
69.35
ATOM
1382
C
LYS
357
56.353
−22.582
90.769
1.00
61.58
ATOM
1383
O
LYS
357
55.735
−23.211
91.630
1.00
61.43
ATOM
1384
N
THR
358
56.463
−21.257
90.778
1.00
57.89
ATOM
1385
CA
THR
358
55.851
−20.434
91.817
1.00
54.10
ATOM
1386
CB
THR
358
56.721
−19.218
92.155
1.00
53.27
ATOM
1387
OG1
THR
358
57.983
−19.666
92.659
1.00
52.66
ATOM
1388
CG2
THR
358
56.045
−18.358
93.202
1.00
53.26
ATOM
1389
C
THR
358
54.500
−19.944
91.317
1.00
51.75
ATOM
1390
O
THR
358
54.412
−19.332
90.257
1.00
51.73
ATOM
1391
N
ILE
359
53.452
−20.221
92.084
1.00
48.72
ATOM
1392
CA
ILE
359
52.100
−19.832
91.707
1.00
45.84
ATOM
1393
CB
ILE
359
51.054
−20.849
92.247
1.00
44.27
ATOM
1394
CG2
ILE
359
49.667
−20.470
91.782
1.00
43.26
ATOM
1395
CG1
ILE
359
51.387
−22.258
91.767
1.00
42.29
ATOM
1396
CD1
ILE
359
51.461
−22.383
90.264
1.00
42.14
ATOM
1397
C
ILE
359
51.732
−18.450
92.228
1.00
45.04
ATOM
1398
O
ILE
359
51.703
−18.231
93.438
1.00
44.85
ATOM
1399
N
ILE
360
51.451
−17.528
91.309
1.00
44.16
ATOM
1400
CA
ILE
360
51.058
−16.163
91.667
1.00
43.62
ATOM
1401
CB
ILE
360
51.930
−15.086
90.968
1.00
41.87
ATOM
1402
CG2
ILE
360
51.486
−13.711
91.399
1.00
41.80
ATOM
1403
CG1
ILE
360
53.401
−15.280
91.297
1.00
40.00
ATOM
1404
CD1
ILE
360
54.176
−15.839
90.143
1.00
41.00
ATOM
1405
C
ILE
360
49.620
−15.898
91.231
1.00
43.95
ATOM
1406
O
ILE
360
49.205
−16.302
90.139
1.00
43.81
ATOM
1407
N
PHE
361
48.859
−15.215
92.076
1.00
43.88
ATOM
1408
CA
PHE
361
47.486
−14.886
91.721
1.00
45.05
ATOM
1409
CB
PHE
361
46.510
−15.333
92.818
1.00
44.55
ATOM
1410
CG
PHE
361
46.421
−16.832
92.991
1.00
43.16
ATOM
1411
CD1
PHE
361
47.047
−17.463
94.059
1.00
41.83
ATOM
1412
CD2
PHE
361
45.723
−17.609
92.074
1.00
41.08
ATOM
1413
CE1
PHE
361
46.978
−18.835
94.207
1.00
39.99
ATOM
1414
CE2
PHE
361
45.650
−18.978
92.216
1.00
39.19
ATOM
1415
CZ
PHE
361
46.280
−19.591
93.284
1.00
39.63
ATOM
1416
C
PHE
361
47.370
−13.381
91.521
1.00
45.78
ATOM
1417
O
PHE
361
47.599
−12.619
92.456
1.00
48.15
ATOM
1418
N
LYS
362
47.032
−12.946
90.310
1.00
44.97
ATOM
1419
CA
LYS
362
46.880
−11.519
90.044
1.00
45.08
ATOM
1420
CB
LYS
362
47.836
−11.058
88.946
1.00
46.05
ATOM
1421
CG
LYS
362
49.297
−11.075
89.307
1.00
46.12
ATOM
1422
CD
LYS
362
50.116
−10.559
88.147
1.00
44.35
ATOM
1423
CE
LYS
362
51.572
−10.516
88.524
1.00
45.15
ATOM
1424
NZ
LYS
362
51.752
−9.677
89.742
1.00
45.33
ATOM
1425
C
LYS
362
45.461
−11.179
89.611
1.00
45.45
ATOM
1426
O
LYS
362
44.719
−12.042
89.138
1.00
45.50
ATOM
1427
N
GLN
363
45.102
−9.907
89.759
1.00
45.24
ATOM
1428
CA
GLN
363
43.781
−9.411
89.380
1.00
44.82
ATOM
1429
CB
GLN
363
43.639
−7.954
89.818
1.00
44.59
ATOM
1430
CG
GLN
363
44.807
−7.064
89.415
1.00
45.02
ATOM
1431
CD
GLN
363
44.428
−5.595
89.372
1.00
45.87
ATOM
1432
OE1
GLN
363
43.555
−5.199
88.600
1.00
47.42
ATOM
1433
NE2
GLN
363
45.079
−4.780
90.199
1.00
44.92
ATOM
1434
C
GLN
363
43.527
−9.506
87.872
1.00
45.01
ATOM
1435
O
GLN
363
44.459
−9.717
87.090
1.00
44.87
ATOM
1436
N
SER
364
42.263
−9.350
87.470
1.00
44.60
ATOM
1437
CA
SER
364
41.895
−9.394
86.052
1.00
43.07
ATOM
1438
CB
SER
364
40.444
−8.956
85.850
1.00
41.38
ATOM
1439
OG
SER
364
40.073
−9.076
84.487
1.00
39.74
ATOM
1440
C
SER
364
42.803
−8.436
85.297
1.00
43.26
ATOM
1441
O
SER
364
43.104
−7.347
85.793
1.00
43.43
ATOM
1442
N
SER
365
43.234
−8.829
84.102
1.00
42.44
ATOM
1443
CA
SER
365
44.116
−7.979
83.312
1.00
41.33
ATOM
1444
CB
SER
365
45.140
−8.846
82.566
1.00
41.58
ATOM
1445
OG
SER
365
44.530
−10.000
82.013
1.00
44.41
ATOM
1446
C
SER
365
43.445
−6.996
82.328
1.00
40.25
ATOM
1447
O
SER
365
44.132
−6.413
81.491
1.00
42.93
ATOM
1448
N
GLY
366
42.130
−6.794
82.424
1.00
36.76
ATOM
1449
CA
GLY
366
41.473
−5.860
81.524
1.00
32.05
ATOM
1450
C
GLY
366
40.321
−6.445
80.741
1.00
31.17
ATOM
1451
O
GLY
366
40.099
−7.652
80.762
1.00
31.00
ATOM
1452
N
GLY
367
39.581
−5.585
80.044
1.00
30.27
ATOM
1453
CA
GLY
367
38.441
−6.040
79.258
1.00
29.70
ATOM
1454
C
GLY
367
37.117
−5.504
79.777
1.00
29.80
ATOM
1455
O
GLY
367
37.087
−4.691
80.702
1.00
31.08
ATOM
1456
N
ASP
368
36.015
−5.954
79.192
1.00
29.13
ATOM
1457
CA
ASP
368
34.699
−5.507
79.626
1.00
31.89
ATOM
1458
CB
ASP
368
33.604
−6.305
78.909
1.00
35.79
ATOM
1459
CG
ASP
368
33.588
−6.073
77.397
1.00
39.65
ATOM
1460
OD1
ASP
368
32.826
−6.784
76.700
1.00
40.00
ATOM
1461
OD2
ASP
368
34.328
−5.187
76.908
1.00
42.73
ATOM
1462
C
ASP
368
34.527
−5.663
81.144
1.00
32.13
ATOM
1463
O
ASP
368
35.139
−6.527
81.757
1.00
32.82
ATOM
1464
N
PRO
369
33.684
−4.821
81.766
1.00
31.85
ATOM
1465
CD
PRO
369
32.993
−3.693
81.120
1.00
30.96
ATOM
1466
CA
PRO
369
33.404
−4.838
83.207
1.00
31.36
ATOM
1467
CB
PRO
369
32.265
−3.842
83.337
1.00
31.63
ATOM
1468
CG
PRO
369
32.613
−2.833
82.289
1.00
31.18
ATOM
1469
C
PRO
369
33.007
−6.203
83.739
1.00
30.91
ATOM
1470
O
PRO
369
33.485
−6.649
84.778
1.00
31.90
ATOM
1471
N
GLU
370
32.112
−6.858
83.023
1.00
30.62
ATOM
1472
CA
GLU
370
31.627
−8.162
83.415
1.00
31.59
ATOM
1473
CB
GLU
370
30.534
−8.585
82.440
1.00
32.54
ATOM
1474
CG
GLU
370
29.303
−7.659
82.445
1.00
34.81
ATOM
1475
CD
GLU
370
29.452
−6.366
81.622
1.00
34.63
ATOM
1476
OE1
GLU
370
28.495
−5.567
81.601
1.00
34.16
ATOM
1477
OE2
GLU
370
30.503
−6.142
80.991
1.00
35.90
ATOM
1478
C
GLU
370
32.718
−9.245
83.519
1.00
32.22
ATOM
1479
O
GLU
370
32.528
−10.259
84.194
1.00
33.09
ATOM
1480
N
ILE
371
33.857
−9.016
82.864
1.00
31.32
ATOM
1481
CA
ILE
371
34.999
−9.943
82.861
1.00
28.31
ATOM
1482
CB
ILE
371
35.579
−10.085
81.422
1.00
28.08
ATOM
1483
CG2
ILE
371
37.098
−10.089
81.437
1.00
27.78
ATOM
1484
CG1
ILE
371
35.037
−11.343
80.779
1.00
28.02
ATOM
1485
CD1
ILE
371
33.555
−11.407
80.819
1.00
30.47
ATOM
1486
C
ILE
371
36.133
−9.506
83.797
1.00
27.21
ATOM
1487
O
ILE
371
36.974
−10.315
84.191
1.00
26.14
ATOM
1488
N
VAL
372
36.158
−8.224
84.138
1.00
26.33
ATOM
1489
CA
VAL
372
37.194
−7.676
85.007
1.00
27.67
ATOM
1490
CB
VAL
372
37.487
−6.200
84.678
1.00
27.14
ATOM
1491
CG1
VAL
372
38.468
−5.636
85.687
1.00
24.67
ATOM
1492
CG2
VAL
372
38.035
−6.078
83.258
1.00
26.38
ATOM
1493
C
VAL
372
36.807
−7.739
86.467
1.00
28.75
ATOM
1494
O
VAL
372
37.662
−7.792
87.355
1.00
29.82
ATOM
1495
N
THR
373
35.506
−7.734
86.709
1.00
29.47
ATOM
1496
CA
THR
373
34.983
−7.770
88.066
1.00
28.66
ATOM
1497
CB
THR
373
34.079
−6.554
88.296
1.00
27.96
ATOM
1498
OG1
THR
373
32.916
−6.668
87.472
1.00
28.85
ATOM
1499
CG2
THR
373
34.801
−5.285
87.888
1.00
26.32
ATOM
1500
C
THR
373
34.166
−9.042
88.221
1.00
28.00
ATOM
1501
O
THR
373
33.806
−9.658
87.211
1.00
28.23
ATOM
1502
N
HIS
374
33.902
−9.453
89.466
1.00
27.55
ATOM
1503
CA
HIS
374
33.075
−10.642
89.723
1.00
26.55
ATOM
1504
CB
HIS
374
33.245
−11.149
91.162
1.00
25.93
ATOM
1505
CG
HIS
374
32.187
−12.121
91.591
1.00
26.09
ATOM
1506
CD2
HIS
374
31.358
−12.121
92.663
1.00
26.47
ATOM
1507
ND1
HIS
374
31.866
−13.243
90.863
1.00
27.70
ATOM
1508
CE1
HIS
374
30.881
−13.892
91.463
1.00
25.87
ATOM
1509
NE2
HIS
374
30.555
−13.232
92.557
1.00
25.26
ATOM
1510
C
HIS
374
31.654
−10.153
89.476
1.00
25.07
ATOM
1511
O
HIS
374
31.071
−9.423
90.268
1.00
25.98
ATOM
1512
N
TRP
375
31.132
−10.546
88.332
1.00
24.08
ATOM
1513
CA
TRP
375
29.829
−10.142
87.866
1.00
24.74
ATOM
1514
CB
TRP
375
29.960
−9.781
86.383
1.00
25.04
ATOM
1515
CG
TRP
375
28.702
−9.478
85.662
1.00
25.75
ATOM
1516
CD2
TRP
375
28.096
−10.271
84.645
1.00
25.29
ATOM
1517
CE2
TRP
375
26.916
−9.609
84.235
1.00
24.75
ATOM
1518
CE3
TRP
375
28.430
−11.488
84.037
1.00
26.21
ATOM
1519
CD1
TRP
375
27.896
−8.390
85.828
1.00
26.87
ATOM
1520
NE1
TRP
375
26.819
−8.457
84.972
1.00
25.73
ATOM
1521
CZ2
TRP
375
26.075
−10.111
83.256
1.00
25.28
ATOM
1522
CZ3
TRP
375
27.591
−11.996
83.057
1.00
25.89
ATOM
1523
CH2
TRP
375
26.424
−11.307
82.678
1.00
26.36
ATOM
1524
C
TRP
375
28.844
−11.268
88.060
1.00
26.93
ATOM
1525
O
TRP
375
29.098
−12.411
87.687
1.00
27.40
ATOM
1526
N
PHE
376
27.707
−10.946
88.646
1.00
28.62
ATOM
1527
CA
PHE
376
26.693
−11.954
88.863
1.00
31.15
ATOM
1528
CB
PHE
376
26.989
−12.736
90.130
1.00
30.11
ATOM
1529
CG
PHE
376
27.135
−11.877
91.332
1.00
30.51
ATOM
1530
CD1
PHE
376
28.310
−11.162
91.547
1.00
30.86
ATOM
1531
CD2
PHE
376
26.090
−11.754
92.241
1.00
30.19
ATOM
1532
CE1
PHE
376
28.448
−10.331
92.652
1.00
29.71
ATOM
1533
CE2
PHE
376
26.209
−10.929
93.352
1.00
30.22
ATOM
1534
CZ
PHE
376
27.393
−10.213
93.560
1.00
30.89
ATOM
1535
C
PHE
376
25.355
−11.279
88.996
1.00
32.83
ATOM
1536
O
PHE
376
25.280
−10.086
89.252
1.00
33.02
ATOM
1537
N
ASN
377
24.299
−12.051
88.809
1.00
35.69
ATOM
1538
CA
ASN
377
22.963
−11.521
88.929
1.00
40.61
ATOM
1539
CB
ASN
377
22.046
−12.178
87.913
1.00
44.38
ATOM
1540
CG
ASN
377
20.647
−11.597
87.940
1.00
48.66
ATOM
1541
OD1
ASN
377
20.426
−10.443
87.542
1.00
48.26
ATOM
1542
ND2
ASN
377
19.689
−12.393
88.420
1.00
51.13
ATOM
1543
C
ASN
377
22.491
−11.855
90.327
1.00
42.23
ATOM
1544
O
ASN
377
22.892
−12.864
90.876
1.00
44.30
ATOM
1545
N
CYS
378
21.643
−11.009
90.901
1.00
44.55
ATOM
1546
CA
CYS
378
21.117
−11.220
92.251
1.00
45.14
ATOM
1547
C
CYS
378
19.934
−10.282
92.488
1.00
43.00
ATOM
1548
O
CYS
378
20.075
−9.066
92.377
1.00
41.28
ATOM
1549
CB
CYS
378
22.203
−10.950
93.302
1.00
49.09
ATOM
1550
SG
CYS
378
21.506
−11.015
94.982
1.00
57.12
ATOM
1551
N
GLY
379
18.773
−10.842
92.819
1.00
41.22
ATOM
1552
CA
GLY
379
17.600
−10.011
93.025
1.00
40.83
ATOM
1553
C
GLY
379
17.246
−9.244
91.753
1.00
40.79
ATOM
1554
O
GLY
379
16.556
−8.222
91.784
1.00
41.26
ATOM
1555
N
GLY
380
17.718
−9.738
90.619
1.00
39.72
ATOM
1556
CA
GLY
380
17.442
−9.059
89.372
1.00
39.79
ATOM
1557
C
GLY
380
18.461
−7.986
89.005
1.00
39.81
ATOM
1558
O
GLY
380
18.544
−7.578
87.842
1.00
39.98
ATOM
1559
N
GLU
381
19.243
−7.524
89.979
1.00
39.10
ATOM
1560
CA
GLU
381
20.244
−6.489
89.712
1.00
38.16
ATOM
1561
CB
GLU
381
20.440
−5.607
90.940
1.00
38.52
ATOM
1562
CG
GLU
381
19.162
−5.139
91.601
1.00
41.28
ATOM
1563
CD
GLU
381
18.327
−4.226
90.728
1.00
43.40
ATOM
1564
OE1
GLU
381
18.904
−3.420
89.963
1.00
44.79
ATOM
1565
OE2
GLU
381
17.083
−4.303
90.827
1.00
44.94
ATOM
1566
C
GLU
381
21.583
−7.123
89.353
1.00
36.75
ATOM
1567
O
GLU
381
21.890
−8.228
89.796
1.00
34.31
ATOM
1568
N
PHE
382
22.382
−6.421
88.556
1.00
34.93
ATOM
1569
CA
PHE
382
23.684
−6.937
88.174
1.00
34.11
ATOM
1570
CB
PHE
382
23.955
−6.685
86.699
1.00
35.03
ATOM
1571
CG
PHE
382
23.062
−7.450
85.796
1.00
35.63
ATOM
1572
CD1
PHE
382
21.868
−6.901
85.351
1.00
37.48
ATOM
1573
CD2
PHE
382
23.392
−8.740
85.415
1.00
37.08
ATOM
1574
CE1
PHE
382
21.007
−7.628
84.534
1.00
38.27
ATOM
1575
CE2
PHE
382
22.543
−9.482
84.600
1.00
38.30
ATOM
1576
CZ
PHE
382
21.343
−8.924
84.156
1.00
38.80
ATOM
1577
C
PHE
382
24.800
−6.316
88.992
1.00
33.85
ATOM
1578
O
PHE
382
25.066
−5.122
88.892
1.00
33.66
ATOM
1579
N
PHE
383
25.463
−7.145
89.788
1.00
33.72
ATOM
1580
CA
PHE
383
26.557
−6.694
90.628
1.00
33.09
ATOM
1581
CB
PHE
383
26.646
−7.546
91.895
1.00
34.99
ATOM
1582
CG
PHE
383
25.462
−7.409
92.806
1.00
38.33
ATOM
1583
CD1
PHE
383
24.183
−7.730
92.364
1.00
39.48
ATOM
1584
CD2
PHE
383
25.619
−6.928
94.103
1.00
40.16
ATOM
1585
CE1
PHE
383
23.079
−7.568
93.195
1.00
39.96
ATOM
1586
CE2
PHE
383
24.517
−6.762
94.942
1.00
39.80
ATOM
1587
CZ
PHE
383
23.247
−7.082
94.484
1.00
40.07
ATOM
1588
C
PHE
383
27.876
−6.775
89.887
1.00
31.86
ATOM
1589
O
PHE
383
28.064
−7.627
89.024
1.00
30.97
ATOM
1590
N
TYR
384
28.779
−5.870
90.233
1.00
31.42
ATOM
1591
CA
TYR
384
30.102
−5.818
89.646
1.00
32.51
ATOM
1592
CB
TYR
384
30.197
−4.673
88.643
1.00
33.51
ATOM
1593
CG
TYR
384
29.350
−4.850
87.399
1.00
35.33
ATOM
1594
CD1
TYR
384
27.961
−4.728
87.451
1.00
36.88
ATOM
1595
CE1
TYR
384
27.177
−4.891
86.311
1.00
36.38
ATOM
1596
CD2
TYR
384
29.938
−5.145
86.170
1.00
35.34
ATOM
1597
CE2
TYR
384
29.165
−5.311
85.023
1.00
36.36
ATOM
1598
CZ
TYR
384
27.784
−5.185
85.102
1.00
37.21
ATOM
1599
OH
TYR
384
27.008
−5.351
83.971
1.00
37.53
ATOM
1600
C
TYR
384
31.033
−5.558
90.815
1.00
33.55
ATOM
1601
O
TYR
384
31.207
−4.404
91.217
1.00
32.94
ATOM
1602
N
CYS
385
31.619
−6.631
91.356
1.00
34.77
ATOM
1603
CA
CYS
385
32.509
−6.549
92.525
1.00
34.65
ATOM
1604
C
CYS
385
33.971
−6.626
92.216
1.00
34.20
ATOM
1605
O
CYS
385
34.433
−7.558
91.565
1.00
35.22
ATOM
1606
CB
CYS
385
32.217
−7.658
93.521
1.00
34.87
ATOM
1607
SG
CYS
385
30.526
−7.663
94.168
1.00
40.52
ATOM
1608
N
ASN
386
34.705
−5.653
92.727
1.00
33.25
ATOM
1609
CA
ASN
386
36.129
−5.598
92.521
1.00
33.13
ATOM
1610
CB
ASN
386
36.645
−4.259
93.011
1.00
35.09
ATOM
1611
CG
ASN
386
38.103
−4.104
92.775
1.00
39.37
ATOM
1612
OD1
ASN
386
38.880
−4.983
93.117
1.00
41.53
ATOM
1613
ND2
ASN
386
38.506
−2.990
92.194
1.00
43.99
ATOM
1614
C
ASN
386
36.802
−6.744
93.280
1.00
32.07
ATOM
1615
O
ASN
386
36.891
−6.718
94.507
1.00
33.16
ATOM
1616
N
SER
387
37.288
−7.746
92.555
1.00
30.06
ATOM
1617
CA
SER
387
37.922
−8.895
93.196
1.00
29.26
ATOM
1618
CB
SER
387
37.505
−10.178
92.478
1.00
28.12
ATOM
1619
OG
SER
387
37.730
−10.093
91.087
1.00
26.31
ATOM
1620
C
SER
387
39.443
−8.867
93.337
1.00
29.50
ATOM
1621
O
SER
387
40.063
−9.889
93.624
1.00
29.39
ATOM
1622
N
THR
388
40.045
−7.702
93.159
1.00
29.97
ATOM
1623
CA
THR
388
41.488
−7.586
93.273
1.00
31.62
ATOM
1624
CB
THR
388
41.929
−6.116
93.190
1.00
32.80
ATOM
1625
OG1
THR
388
41.734
−5.630
91.849
1.00
31.68
ATOM
1626
CG2
THR
388
43.392
−5.980
93.590
1.00
31.85
ATOM
1627
C
THR
388
42.038
−8.194
94.561
1.00
33.05
ATOM
1628
O
THR
388
43.100
−8.816
94.553
1.00
33.91
ATOM
1629
N
GLN
389
41.320
−8.027
95.667
1.00
34.67
ATOM
1630
CA
GLN
389
41.792
−8.574
96.944
1.00
37.35
ATOM
1631
CB
GLN
389
40.957
−8.065
98.124
1.00
36.04
ATOM
1632
CG
GLN
389
40.860
−6.578
98.266
1.00
34.05
ATOM
1633
CD
GLN
389
39.773
−6.202
99.241
1.00
34.91
ATOM
1634
OE1
GLN
389
39.964
−6.271
100.451
1.00
37.19
ATOM
1635
NE2
GLN
389
38.609
−5.826
98.720
1.00
36.20
ATOM
1636
C
GLN
389
41.779
−10.101
97.011
1.00
38.08
ATOM
1637
O
GLN
389
42.422
−10.687
97.882
1.00
40.01
ATOM
1638
N
LEU
390
41.042
−10.752
96.124
1.00
37.43
ATOM
1639
CA
LEU
390
40.994
−12.199
96.175
1.00
38.01
ATOM
1640
CB
LEU
390
39.663
−12.699
95.613
1.00
37.92
ATOM
1641
CG
LEU
390
38.396
−12.318
96.392
1.00
37.01
ATOM
1642
CD1
LEU
390
37.175
−12.765
95.614
1.00
35.68
ATOM
1643
CD2
LEU
390
38.399
−12.959
97.764
1.00
35.67
ATOM
1644
C
LEU
390
42.163
−12.816
95.415
1.00
39.31
ATOM
1645
O
LEU
390
42.692
−13.863
95.801
1.00
40.54
ATOM
1646
N
PHE
391
42.583
−12.150
94.347
1.00
39.70
ATOM
1647
CA
PHE
391
43.680
−12.644
93.528
1.00
38.54
ATOM
1648
CB
PHE
391
43.206
−12.794
92.092
1.00
37.22
ATOM
1649
CG
PHE
391
41.913
−13.532
91.984
1.00
37.31
ATOM
1650
CD1
PHE
391
40.707
−12.871
92.177
1.00
38.01
ATOM
1651
CD2
PHE
391
41.897
−14.907
91.784
1.00
37.44
ATOM
1652
CE1
PHE
391
39.507
−13.565
92.179
1.00
37.83
ATOM
1653
CE2
PHE
391
40.699
−15.613
91.786
1.00
37.13
ATOM
1654
CZ
PHE
391
39.501
−14.939
91.986
1.00
38.34
ATOM
1655
C
PHE
391
44.848
−11.691
93.622
1.00
39.15
ATOM
1656
O
PHE
391
45.093
−10.874
92.724
1.00
37.81
ATOM
1657
N
ASN
392
45.554
−11.808
94.742
1.00
40.04
ATOM
1658
CA
ASN
392
46.709
−10.980
95.038
1.00
40.61
ATOM
1659
CB
ASN
392
46.243
−9.647
95.650
1.00
40.52
ATOM
1660
CG
ASN
392
47.401
−8.713
95.990
1.00
42.11
ATOM
1661
OD1
ASN
392
48.388
−8.643
95.255
1.00
42.90
ATOM
1662
ND2
ASN
392
47.272
−7.978
97.093
1.00
42.11
ATOM
1663
C
ASN
392
47.615
−11.736
96.006
1.00
40.17
ATOM
1664
O
ASN
392
47.771
−11.336
97.148
1.00
40.62
ATOM
1665
N
SER
393
48.205
−12.837
95.558
1.00
40.28
ATOM
1666
CA
SER
393
49.085
−13.598
96.436
1.00
41.43
ATOM
1667
CB
SER
393
48.261
−14.448
97.403
1.00
40.63
ATOM
1668
OG
SER
393
47.328
−15.262
96.718
1.00
40.80
ATOM
1669
C
SER
393
50.077
−14.479
95.687
1.00
42.79
ATOM
1670
O
SER
393
49.819
−14.908
94.556
1.00
42.31
ATOM
1671
N
THR
394
51.212
−14.737
96.333
1.00
43.79
ATOM
1672
CA
THR
394
52.277
−15.551
95.756
1.00
45.04
ATOM
1673
CB
THR
394
53.574
−14.737
95.642
1.00
45.96
ATOM
1674
OG1
THR
394
53.333
−13.573
94.833
1.00
46.10
ATOM
1675
CG2
THR
394
54.688
−15.584
95.026
1.00
45.27
ATOM
1676
C
THR
394
52.541
−16.790
96.602
1.00
45.64
ATOM
1677
O
THR
394
52.906
−16.684
97.769
1.00
44.76
ATOM
1678
N
TRP
395
52.378
−17.964
95.996
1.00
47.09
ATOM
1679
CA
TRP
395
52.548
−19.228
96.705
1.00
47.76
ATOM
1680
CB
TRP
395
51.288
−20.068
96.527
1.00
41.92
ATOM
1681
CG
TRP
395
50.107
−19.326
96.976
1.00
38.28
ATOM
1682
CD2
TRP
395
49.405
−19.506
98.205
1.00
36.22
ATOM
1683
CE2
TRP
395
48.415
−18.503
98.268
1.00
36.46
ATOM
1684
CE3
TRP
395
49.514
−20.414
99.258
1.00
33.85
ATOM
1685
CD1
TRP
395
49.532
−18.258
96.357
1.00
37.38
ATOM
1686
NE1
TRP
395
48.517
−17.754
97.126
1.00
36.41
ATOM
1687
CZ2
TRP
395
47.539
−18.387
99.348
1.00
34.01
ATOM
1688
CZ3
TRP
395
48.647
−20.297
100.324
1.00
33.66
ATOM
1689
CH2
TRP
395
47.670
−19.290
100.361
1.00
33.40
ATOM
1690
C
TRP
395
53.761
−20.066
96.339
1.00
51.43
ATOM
1691
O
TRP
395
54.159
−20.124
95.170
1.00
52.73
ATOM
1692
N
PHE
396
54.339
−20.710
97.358
1.00
54.22
ATOM
1693
CA
PHE
396
55.491
−21.589
97.190
1.00
56.04
ATOM
1694
CB
PHE
396
55.138
−22.681
96.186
1.00
54.94
ATOM
1695
CG
PHE
396
53.790
−23.305
96.422
1.00
55.63
ATOM
1696
CD1
PHE
396
53.083
−23.883
95.373
1.00
56.03
ATOM
1697
CD2
PHE
396
53.226
−23.325
97.699
1.00
56.08
ATOM
1698
CE1
PHE
396
51.830
−24.480
95.591
1.00
56.77
ATOM
1699
CE2
PHE
396
51.974
−23.917
97.930
1.00
56.41
ATOM
1700
CZ
PHE
396
51.275
−24.495
96.872
1.00
56.06
ATOM
1701
C
PHE
396
56.708
−20.813
96.713
1.00
58.81
ATOM
1702
O
PHE
396
57.523
−21.322
95.938
1.00
59.35
ATOM
1703
N
ASN
397
56.815
−19.570
97.172
1.00
61.45
ATOM
1704
CA
ASN
397
57.932
−18.717
96.802
1.00
63.89
ATOM
1705
CB
ASN
397
57.462
−17.262
96.713
1.00
65.82
ATOM
1706
CG
ASN
397
58.568
−16.310
96.270
1.00
68.51
ATOM
1707
OD1
ASN
397
58.333
−15.112
96.075
1.00
69.99
ATOM
1708
ND2
ASN
397
59.782
−16.839
96.110
1.00
68.62
ATOM
1709
C
ASN
397
59.052
−18.854
97.837
1.00
64.94
ATOM
1710
O
ASN
397
59.583
−19.946
98.065
1.00
64.91
ATOM
1711
N
GLY
410
45.948
−11.180
107.879
1.00
61.02
ATOM
1712
CA
GLY
410
45.413
−9.847
107.656
1.00
62.50
ATOM
1713
C
GLY
410
44.155
−9.569
108.466
1.00
62.44
ATOM
1714
O
GLY
410
44.097
−9.849
109.668
1.00
63.35
ATOM
1715
N
SER
411
43.145
−9.007
107.814
1.00
61.14
ATOM
1716
CA
SER
411
41.893
−8.720
108.488
1.00
60.04
ATOM
1717
CB
SER
411
41.252
−7.461
107.913
1.00
61.29
ATOM
1718
OG
SER
411
39.982
−7.232
108.499
1.00
62.93
ATOM
1719
C
SER
411
40.959
−9.902
108.295
1.00
59.15
ATOM
1720
O
SER
411
40.857
−10.448
107.197
1.00
59.05
ATOM
1721
N
ASP
412
40.278
−10.285
109.369
1.00
57.82
ATOM
1722
CA
ASP
412
39.338
−11.406
109.376
1.00
56.24
ATOM
1723
CB
ASP
412
38.360
−11.213
110.532
1.00
59.37
ATOM
1724
CG
ASP
412
37.032
−11.908
110.298
1.00
63.07
ATOM
1725
OD1
ASP
412
37.031
−13.136
110.041
1.00
64.07
ATOM
1726
OD2
ASP
412
35.990
−11.214
110.371
1.00
65.25
ATOM
1727
C
ASP
412
38.556
−11.681
108.082
1.00
53.55
ATOM
1728
O
ASP
412
38.694
−12.746
107.475
1.00
52.85
ATOM
1729
N
THR
413
37.715
−10.735
107.680
1.00
50.45
ATOM
1730
CA
THR
413
36.918
−10.892
106.472
1.00
46.99
ATOM
1731
CB
THR
413
35.415
−10.527
106.742
1.00
46.65
ATOM
1732
OG1
THR
413
34.929
−9.666
105.703
1.00
46.90
ATOM
1733
CG2
THR
413
35.247
−9.813
108.078
1.00
44.53
ATOM
1734
C
THR
413
37.456
−10.014
105.337
1.00
44.78
ATOM
1735
O
THR
413
38.021
−8.954
105.580
1.00
45.19
ATOM
1736
N
ILE
414
37.311
−10.471
104.099
1.00
41.90
ATOM
1737
CA
ILE
414
37.744
−9.684
102.949
1.00
39.73
ATOM
1738
CB
ILE
414
38.299
−10.564
101.813
1.00
38.13
ATOM
1739
CG2
ILE
414
38.798
−9.697
100.690
1.00
36.56
ATOM
1740
CG1
ILE
414
39.464
−11.408
102.316
1.00
37.94
ATOM
1741
CD1
ILE
414
39.966
−12.403
101.300
1.00
34.67
ATOM
1742
C
ILE
414
36.474
−9.007
102.444
1.00
39.45
ATOM
1743
O
ILE
414
35.541
−9.682
102.008
1.00
38.16
ATOM
1744
N
THR
415
36.420
−7.683
102.526
1.00
39.33
ATOM
1745
CA
THR
415
35.237
−6.956
102.071
1.00
39.02
ATOM
1746
CB
THR
415
34.868
−5.782
103.045
1.00
40.55
ATOM
1747
OG1
THR
415
34.451
−6.313
104.313
1.00
41.85
ATOM
1748
CG2
THR
415
33.731
−4.942
102.483
1.00
39.85
ATOM
1749
C
THR
415
35.487
−6.410
100.671
1.00
37.52
ATOM
1750
O
THR
415
36.386
−5.592
100.458
1.00
36.96
ATOM
1751
N
LEU
416
34.683
−6.887
99.722
1.00
35.70
ATOM
1752
CA
LEU
416
34.772
−6.480
98.323
1.00
33.93
ATOM
1753
CB
LEU
416
34.459
−7.669
97.422
1.00
35.45
ATOM
1754
CG
LEU
416
35.609
−8.553
96.946
1.00
36.03
ATOM
1755
CD1
LEU
416
36.708
−8.616
98.004
1.00
35.17
ATOM
1756
CD2
LEU
416
35.046
−9.933
96.610
1.00
35.12
ATOM
1757
C
LEU
416
33.831
−5.340
97.949
1.00
31.99
ATOM
1758
O
LEU
416
32.631
−5.392
98.222
1.00
31.87
ATOM
1759
N
PRO
417
34.366
−4.285
97.319
1.00
29.92
ATOM
1760
CD
PRO
417
35.782
−3.965
97.067
1.00
27.19
ATOM
1761
CA
PRO
417
33.507
−3.169
96.929
1.00
28.26
ATOM
1762
CB
PRO
417
34.509
−2.052
96.705
1.00
24.49
ATOM
1763
CG
PRO
417
35.678
−2.776
96.162
1.00
23.69
ATOM
1764
C
PRO
417
32.747
−3.548
95.654
1.00
28.94
ATOM
1765
O
PRO
417
33.305
−4.215
94.781
1.00
29.04
ATOM
1766
N
CYS
418
31.476
−3.166
95.553
1.00
30.16
ATOM
1767
CA
CYS
418
30.702
−3.472
94.348
1.00
33.10
ATOM
1768
C
CYS
418
29.782
−2.338
93.978
1.00
32.71
ATOM
1769
O
CYS
418
29.610
−1.387
94.731
1.00
33.13
ATOM
1770
CB
CYS
418
29.808
−4.704
94.510
1.00
35.70
ATOM
1771
SG
CYS
418
30.459
−6.095
95.454
1.00
40.35
ATOM
1772
N
ARG
419
29.167
−2.479
92.812
1.00
33.12
ATOM
1773
CA
ARG
419
28.226
−1.499
92.315
1.00
33.48
ATOM
1774
CB
ARG
419
28.937
−0.474
91.418
1.00
35.57
ATOM
1775
CG
ARG
419
28.028
0.673
91.009
1.00
42.11
ATOM
1776
CD
ARG
419
28.395
1.296
89.654
1.00
47.71
ATOM
1777
NE
ARG
419
29.270
2.464
89.754
1.00
50.54
ATOM
1778
CZ
ARG
419
30.576
2.412
90.009
1.00
50.62
ATOM
1779
NH1
ARG
419
31.178
1.240
90.189
1.00
50.07
ATOM
1780
NH2
ARG
419
31.279
3.538
90.093
1.00
49.54
ATOM
1781
C
ARG
419
27.163
−2.223
91.501
1.00
31.21
ATOM
1782
O
ARG
419
27.453
−3.223
90.848
1.00
28.57
ATOM
1783
N
ILE
420
25.929
−1.736
91.567
1.00
30.97
ATOM
1784
CA
ILE
420
24.845
−2.301
90.759
1.00
31.92
ATOM
1785
CB
ILE
420
23.459
−2.255
91.482
1.00
31.58
ATOM
1786
CG2
ILE
420
22.341
−2.527
90.491
1.00
29.56
ATOM
1787
CG1
ILE
420
23.396
−3.308
92.583
1.00
32.48
ATOM
1788
CD1
ILE
420
24.525
−3.201
93.579
1.00
35.47
ATOM
1789
C
ILE
420
24.793
−1.378
89.542
1.00
31.56
ATOM
1790
O
ILE
420
24.866
−0.161
89.687
1.00
31.84
ATOM
1791
N
LYS
421
24.687
−1.938
88.349
1.00
30.80
ATOM
1792
CA
LYS
421
24.626
−1.104
87.163
1.00
31.04
ATOM
1793
CB
LYS
421
25.808
−1.418
86.259
1.00
32.69
ATOM
1794
CG
LYS
421
27.164
−1.194
86.883
1.00
32.84
ATOM
1795
CD
LYS
421
28.220
−1.316
85.790
1.00
33.11
ATOM
1796
CE
LYS
421
29.583
−0.872
86.271
1.00
32.74
ATOM
1797
NZ
LYS
421
30.553
−0.859
85.147
1.00
32.81
ATOM
1798
C
LYS
421
23.320
−1.330
86.401
1.00
30.54
ATOM
1799
O
LYS
421
22.720
−2.408
86.503
1.00
30.70
ATOM
1800
N
GLN
422
22.879
−0.319
85.651
1.00
29.64
ATOM
1801
CA
GLN
422
21.652
−0.428
84.859
1.00
30.52
ATOM
1802
CB
GLN
422
20.803
0.838
84.969
1.00
30.67
ATOM
1803
CG
GLN
422
20.065
0.997
86.279
1.00
32.13
ATOM
1804
CD
GLN
422
20.998
1.157
87.466
1.00
33.77
ATOM
1805
OE1
GLN
422
21.823
2.081
87.514
1.00
30.92
ATOM
1806
NE2
GLN
422
20.869
0.255
88.438
1.00
34.85
ATOM
1807
C
GLN
422
21.989
−0.669
83.395
1.00
31.34
ATOM
1808
O
GLN
422
21.162
−1.159
82.630
1.00
31.50
ATOM
1809
N
ILE
423
23.213
−0.321
83.017
1.00
32.09
ATOM
1810
CA
ILE
423
23.681
−0.501
81.650
1.00
31.47
ATOM
1811
CB
ILE
423
24.220
0.825
81.125
1.00
30.44
ATOM
1812
CG2
ILE
423
24.767
0.662
79.725
1.00
29.43
ATOM
1813
CG1
ILE
423
23.084
1.842
81.151
1.00
29.90
ATOM
1814
CD1
ILE
423
23.454
3.193
80.628
1.00
30.47
ATOM
1815
C
ILE
423
24.727
−1.625
81.564
1.00
32.00
ATOM
1816
O
ILE
423
25.905
−1.453
81.856
1.00
33.10
ATOM
1817
N
ILE
424
24.241
−2.785
81.149
1.00
33.21
ATOM
1818
CA
ILE
424
24.995
−4.022
81.017
1.00
33.92
ATOM
1819
CB
ILE
424
24.055
−5.212
81.346
1.00
34.97
ATOM
1820
CG2
ILE
424
24.828
−6.487
81.526
1.00
35.83
ATOM
1821
CG1
ILE
424
23.264
−4.900
82.605
1.00
37.56
ATOM
1822
CD1
ILE
424
24.141
−4.483
83.764
1.00
40.47
ATOM
1823
C
ILE
424
25.529
−4.276
79.609
1.00
33.77
ATOM
1824
O
ILE
424
25.094
−3.670
78.644
1.00
34.71
ATOM
1825
N
ASN
425
26.481
−5.194
79.515
1.00
34.13
ATOM
1826
CA
ASN
425
27.033
−5.649
78.244
1.00
33.45
ATOM
1827
CB
ASN
425
28.559
−5.655
78.279
1.00
33.20
ATOM
1828
CG
ASN
425
29.174
−4.556
77.438
1.00
32.66
ATOM
1829
OD1
ASN
425
28.619
−4.149
76.414
1.00
30.45
ATOM
1830
ND2
ASN
425
30.346
−4.087
77.855
1.00
32.53
ATOM
1831
C
ASN
425
26.536
−7.081
78.347
1.00
33.79
ATOM
1832
O
ASN
425
27.053
−7.826
79.167
1.00
33.77
ATOM
1833
N
MET
426
25.539
−7.471
77.554
1.00
35.05
ATOM
1834
CA
MET
426
24.974
−8.827
77.653
1.00
36.48
ATOM
1835
CB
MET
426
23.788
−8.980
76.698
1.00
37.46
ATOM
1836
CG
MET
426
22.690
−7.954
76.921
1.00
42.17
ATOM
1837
SD
MET
426
21.033
−8.496
76.443
1.00
47.19
ATOM
1838
CE
MET
426
21.110
−8.248
74.701
1.00
47.57
ATOM
1839
C
MET
426
25.928
−10.006
77.447
1.00
37.83
ATOM
1840
O
MET
426
27.017
−9.867
76.885
1.00
37.54
ATOM
1841
N
TRP
427
25.506
−11.176
77.916
1.00
39.73
ATOM
1842
CA
TRP
427
26.304
−12.386
77.770
1.00
41.17
ATOM
1843
CB
TRP
427
26.323
−13.179
79.085
1.00
42.99
ATOM
1844
CG
TRP
427
24.959
−13.556
79.621
1.00
45.82
ATOM
1845
CD2
TRP
427
24.303
−14.822
79.485
1.00
46.80
ATOM
1846
CE2
TRP
427
23.034
−14.709
80.100
1.00
47.00
ATOM
1847
CE3
TRP
427
24.662
−16.044
78.899
1.00
47.97
ATOM
1848
CD1
TRP
427
24.087
−12.748
80.300
1.00
47.03
ATOM
1849
NE1
TRP
427
22.929
−13.434
80.591
1.00
47.49
ATOM
1850
CZ2
TRP
427
22.124
−15.763
80.143
1.00
47.71
ATOM
1851
CZ3
TRP
427
23.756
−17.097
78.944
1.00
48.88
ATOM
1852
CH2
TRP
427
22.500
−16.947
79.562
1.00
49.07
ATOM
1853
C
TRP
427
25.812
−13.284
76.632
1.00
41.19
ATOM
1854
O
TRP
427
26.607
−13.964
76.000
1.00
41.60
ATOM
1855
N
CYS
428
24.509
−13.272
76.363
1.00
42.00
ATOM
1856
CA
CYS
428
23.922
−14.101
75.308
1.00
44.36
ATOM
1857
C
CYS
428
24.410
−13.749
73.917
1.00
44.00
ATOM
1858
O
CYS
428
24.887
−14.616
73.176
1.00
44.48
ATOM
1859
CB
CYS
428
22.394
−14.023
75.381
1.00
47.62
ATOM
1860
SG
CYS
428
21.874
−14.854
76.914
1.00
57.16
ATOM
1861
N
LYS
429
24.290
−12.479
73.557
1.00
43.21
ATOM
1862
CA
LYS
429
24.750
−12.015
72.263
1.00
41.60
ATOM
1863
CB
LYS
429
23.569
−11.882
71.307
1.00
42.35
ATOM
1864
CG
LYS
429
22.384
−11.156
71.883
1.00
43.72
ATOM
1865
CD
LYS
429
21.248
−11.148
70.901
1.00
45.78
ATOM
1866
CE
LYS
429
20.053
−10.418
71.475
1.00
47.56
ATOM
1867
NZ
LYS
429
18.901
−10.405
70.517
1.00
50.92
ATOM
1868
C
LYS
429
25.423
−10.673
72.495
1.00
40.41
ATOM
1869
O
LYS
429
25.256
−10.073
73.553
1.00
40.49
ATOM
1870
N
VAL
430
26.193
−10.213
71.521
1.00
39.52
ATOM
1871
CA
VAL
430
26.879
−8.944
71.645
1.00
39.11
ATOM
1872
CB
VAL
430
27.937
−8.791
70.532
1.00
37.84
ATOM
1873
CG1
VAL
430
28.489
−7.380
70.507
1.00
39.67
ATOM
1874
CG2
VAL
430
29.073
−9.761
70.743
1.00
35.62
ATOM
1875
C
VAL
430
25.914
−7.764
71.573
1.00
40.33
ATOM
1876
O
VAL
430
25.783
−7.136
70.539
1.00
42.24
ATOM
1877
N
CYS
431
25.211
−7.470
72.657
1.00
41.16
ATOM
1878
CA
CYS
431
24.291
−6.326
72.682
1.00
43.40
ATOM
1879
C
CYS
431
24.499
−5.530
73.970
1.00
42.17
ATOM
1880
O
CYS
431
25.000
−6.062
74.964
1.00
43.09
ATOM
1881
CB
CYS
431
22.835
−6.780
72.668
1.00
48.10
ATOM
1882
SG
CYS
431
22.257
−7.836
71.299
1.00
60.95
ATOM
1883
N
LYS
432
24.119
−4.257
73.960
1.00
38.87
ATOM
1884
CA
LYS
432
24.226
−3.454
75.164
1.00
36.15
ATOM
1885
CB
LYS
432
24.860
−2.104
74.846
1.00
35.67
ATOM
1886
CG
LYS
432
25.975
−1.723
75.807
1.00
37.19
ATOM
1887
CD
LYS
432
26.857
−0.647
75.192
1.00
39.70
ATOM
1888
CE
LYS
432
28.075
−0.335
76.058
1.00
42.82
ATOM
1889
NZ
LYS
432
28.992
−1.509
76.255
1.00
42.87
ATOM
1890
C
LYS
432
22.794
−3.297
75.680
1.00
35.02
ATOM
1891
O
LYS
432
21.888
−3.024
74.909
1.00
35.60
ATOM
1892
N
ALA
433
22.574
−3.497
76.972
1.00
33.36
ATOM
1893
CA
ALA
433
21.226
−3.385
77.500
1.00
33.09
ATOM
1894
CB
ALA
433
20.714
−4.753
77.881
1.00
33.61
ATOM
1895
C
ALA
433
21.156
−2.460
78.696
1.00
34.02
ATOM
1896
O
ALA
433
22.129
−2.309
79.420
1.00
35.31
ATOM
1897
N
MET
434
20.006
−1.830
78.908
1.00
34.39
ATOM
1898
CA
MET
434
19.853
−0.927
80.043
1.00
34.19
ATOM
1899
CB
MET
434
19.688
0.522
79.577
1.00
34.29
ATOM
1900
CG
MET
434
19.537
1.519
80.722
1.00
35.19
ATOM
1901
SD
MET
434
18.772
3.088
80.230
1.00
38.57
ATOM
1902
CE
MET
434
17.017
2.778
80.598
1.00
37.43
ATOM
1903
C
MET
434
18.626
−1.328
80.841
1.00
34.05
ATOM
1904
O
MET
434
17.522
−1.387
80.307
1.00
35.74
ATOM
1905
N
TYR
435
18.817
−1.602
82.123
1.00
32.51
ATOM
1906
CA
TYR
435
17.709
−1.984
82.973
1.00
30.96
ATOM
1907
CB
TYR
435
18.106
−3.184
83.822
1.00
29.29
ATOM
1908
CG
TYR
435
18.339
−4.417
82.992
1.00
25.84
ATOM
1909
CD1
TYR
435
19.560
−4.636
82.365
1.00
25.45
ATOM
1910
CE1
TYR
435
19.745
−5.711
81.524
1.00
24.61
ATOM
1911
CD2
TYR
435
17.311
−5.314
82.760
1.00
23.29
ATOM
1912
CE2
TYR
435
17.482
−6.382
81.924
1.00
24.52
ATOM
1913
CZ
TYR
435
18.699
−6.581
81.305
1.00
24.68
ATOM
1914
OH
TYR
435
18.847
−7.648
80.450
1.00
26.95
ATOM
1915
C
TYR
435
17.313
−0.828
83.859
1.00
32.33
ATOM
1916
O
TYR
435
18.001
0.195
83.892
1.00
33.56
ATOM
1917
N
ALA
436
16.203
−0.984
84.576
1.00
32.62
ATOM
1918
CA
ALA
436
15.736
0.067
85.473
1.00
33.64
ATOM
1919
CB
ALA
436
14.236
−0.064
85.698
1.00
31.13
ATOM
1920
C
ALA
436
16.494
−0.003
86.813
1.00
35.55
ATOM
1921
O
ALA
436
17.025
−1.058
87.199
1.00
36.85
ATOM
1922
N
PRO
437
16.580
1.132
87.527
1.00
35.03
ATOM
1923
CD
PRO
437
16.171
2.473
87.084
1.00
34.29
ATOM
1924
CA
PRO
437
17.270
1.198
88.817
1.00
34.44
ATOM
1925
CB
PRO
437
17.150
2.665
89.182
1.00
35.20
ATOM
1926
CG
PRO
437
17.130
3.339
87.833
1.00
35.19
ATOM
1927
C
PRO
437
16.572
0.287
89.825
1.00
35.06
ATOM
1928
O
PRO
437
15.471
−0.200
89.562
1.00
36.23
ATOM
1929
N
PRO
438
17.188
0.051
90.994
1.00
33.79
ATOM
1930
CD
PRO
438
18.576
0.364
91.356
1.00
33.35
ATOM
1931
CA
PRO
438
16.587
−0.820
92.008
1.00
34.09
ATOM
1932
CB
PRO
438
17.729
−1.028
92.994
1.00
33.97
ATOM
1933
CG
PRO
438
18.947
−0.849
92.167
1.00
33.01
ATOM
1934
C
PRO
438
15.343
−0.263
92.694
1.00
35.40
ATOM
1935
O
PRO
438
15.116
0.945
92.706
1.00
35.71
ATOM
1936
N
ILE
439
14.524
−1.151
93.253
1.00
36.30
ATOM
1937
CA
ILE
439
13.333
−0.707
93.962
1.00
36.39
ATOM
1938
CB
ILE
439
12.008
−1.142
93.261
1.00
34.37
ATOM
1939
CG2
ILE
439
12.003
−0.699
91.836
1.00
34.23
ATOM
1940
CG1
ILE
439
11.845
−2.653
93.288
1.00
35.39
ATOM
1941
CD1
ILE
439
10.469
−3.098
92.843
1.00
34.29
ATOM
1942
C
ILE
439
13.367
−1.242
95.393
1.00
37.68
ATOM
1943
O
ILE
439
12.507
−0.911
96.204
1.00
39.13
ATOM
1944
N
SER
440
14.364
−2.062
95.705
1.00
37.37
ATOM
1945
CA
SER
440
14.491
−2.584
97.057
1.00
39.32
ATOM
1946
CB
SER
440
14.604
−4.104
97.054
1.00
40.44
ATOM
1947
OG
SER
440
14.933
−4.568
98.362
1.00
40.66
ATOM
1948
C
SER
440
15.707
−2.011
97.774
1.00
40.33
ATOM
1949
O
SER
440
16.679
−1.597
97.135
1.00
41.36
ATOM
1950
N
GLY
441
15.646
−1.994
99.102
1.00
40.54
ATOM
1951
CA
GLY
441
16.752
−1.482
99.890
1.00
42.17
ATOM
1952
C
GLY
441
17.425
−2.604
100.659
1.00
43.06
ATOM
1953
O
GLY
441
18.367
−2.392
101.437
1.00
42.78
ATOM
1954
N
GLN
442
16.920
−3.811
100.439
1.00
43.64
ATOM
1955
CA
GLN
442
17.445
−4.997
101.085
1.00
44.67
ATOM
1956
CB
GLN
442
16.475
−5.475
102.175
1.00
45.38
ATOM
1957
CG
GLN
442
16.864
−5.030
103.587
1.00
47.90
ATOM
1958
CD
GLN
442
15.750
−5.219
104.621
1.00
49.44
ATOM
1959
OE1
GLN
442
14.751
−4.495
104.599
1.00
50.66
ATOM
1960
NE2
GLN
442
15.921
−6.190
105.530
1.00
47.39
ATOM
1961
C
GLN
442
17.679
−6.080
100.035
1.00
44.84
ATOM
1962
O
GLN
442
16.909
−7.032
99.904
1.00
44.57
ATOM
1963
N
ILE
443
18.755
−5.908
99.278
1.00
45.49
ATOM
1964
CA
ILE
443
19.132
−6.851
98.236
1.00
46.47
ATOM
1965
CB
ILE
443
19.492
−6.092
96.941
1.00
45.56
ATOM
1966
CG2
ILE
443
20.064
−7.039
95.908
1.00
44.09
ATOM
1967
CG1
ILE
443
18.238
−5.392
96.411
1.00
45.07
ATOM
1968
CD1
ILE
443
18.433
−4.604
95.153
1.00
44.19
ATOM
1969
C
ILE
443
20.328
−7.651
98.744
1.00
47.21
ATOM
1970
O
ILE
443
21.449
−7.142
98.782
1.00
47.84
ATOM
1971
N
ARG
444
20.087
−8.899
99.135
1.00
47.05
ATOM
1972
CA
ARG
444
21.150
−9.732
99.681
1.00
48.36
ATOM
1973
CB
ARG
444
20.856
−10.036
101.152
1.00
50.00
ATOM
1974
CG
ARG
444
20.436
−8.837
101.994
1.00
52.86
ATOM
1975
CD
ARG
444
21.439
−8.535
103.105
1.00
55.04
ATOM
1976
NE
ARG
444
20.951
−7.500
104.017
1.00
59.88
ATOM
1977
CZ
ARG
444
20.629
−6.255
103.659
1.00
61.86
ATOM
1978
NH1
ARG
444
20.193
−5.391
104.570
1.00
62.57
ATOM
1979
NH2
ARG
444
20.741
−5.862
102.395
1.00
62.40
ATOM
1980
C
ARG
444
21.361
−11.052
98.948
1.00
48.73
ATOM
1981
O
ARG
444
20.405
−11.671
98.481
1.00
49.67
ATOM
1982
N
CYS
445
22.619
−11.479
98.849
1.00
48.63
ATOM
1983
CA
CYS
445
22.956
−12.749
98.212
1.00
47.62
ATOM
1984
C
CYS
445
24.029
−13.502
98.946
1.00
45.78
ATOM
1985
O
CYS
445
25.207
−13.129
98.931
1.00
45.76
ATOM
1986
CB
CYS
445
23.392
−12.574
96.762
1.00
50.80
ATOM
1987
SG
CYS
445
21.966
−12.871
95.692
1.00
57.24
ATOM
1988
N
SER
446
23.595
−14.574
99.589
1.00
42.24
ATOM
1989
CA
SER
446
24.471
−15.438
100.339
1.00
39.56
ATOM
1990
CB
SER
446
23.764
−15.885
101.600
1.00
40.45
ATOM
1991
OG
SER
446
22.870
−14.868
102.024
1.00
43.28
ATOM
1992
C
SER
446
24.667
−16.613
99.417
1.00
37.50
ATOM
1993
O
SER
446
23.767
−17.424
99.252
1.00
37.85
ATOM
1994
N
SER
447
25.833
−16.693
98.795
1.00
34.81
ATOM
1995
CA
SER
447
26.095
−17.780
97.881
1.00
33.45
ATOM
1996
CB
SER
447
26.331
−17.227
96.485
1.00
34.56
ATOM
1997
OG
SER
447
25.323
−16.307
96.128
1.00
36.68
ATOM
1998
C
SER
447
27.300
−18.588
98.300
1.00
32.91
ATOM
1999
O
SER
447
28.088
−18.178
99.151
1.00
33.16
ATOM
2000
N
ASN
448
27.432
−19.755
97.697
1.00
32.65
ATOM
2001
CA
ASN
448
28.561
−20.620
97.970
1.00
33.16
ATOM
2002
CB
ASN
448
28.088
−22.019
98.361
1.00
35.97
ATOM
2003
CG
ASN
448
27.950
−22.184
99.852
1.00
41.24
ATOM
2004
OD1
ASN
448
28.938
−22.162
100.574
1.00
42.95
ATOM
2005
ND2
ASN
448
26.727
−22.357
100.331
1.00
46.28
ATOM
2006
C
ASN
448
29.444
−20.706
96.731
1.00
31.71
ATOM
2007
O
ASN
448
29.005
−21.162
95.668
1.00
30.58
ATOM
2008
N
ILE
449
30.675
−20.222
96.862
1.00
29.84
ATOM
2009
CA
ILE
449
31.645
−20.292
95.772
1.00
27.37
ATOM
2010
CB
ILE
449
32.980
−19.595
96.137
1.00
25.12
ATOM
2011
CG2
ILE
449
34.005
−19.817
95.040
1.00
24.87
ATOM
2012
CG1
ILE
449
32.766
−18.110
96.374
1.00
22.91
ATOM
2013
CD1
ILE
449
34.006
−17.435
96.882
1.00
20.04
ATOM
2014
C
ILE
449
31.929
−21.784
95.734
1.00
27.61
ATOM
2015
O
ILE
449
32.203
−22.373
96.785
1.00
29.12
ATOM
2016
N
THR
450
31.854
−22.409
94.567
1.00
25.09
ATOM
2017
CA
THR
450
32.134
−23.836
94.501
1.00
24.31
ATOM
2018
CB
THR
450
30.832
−24.667
94.295
1.00
24.01
ATOM
2019
OG1
THR
450
30.135
−24.223
93.121
1.00
23.07
ATOM
2020
CG2
THR
450
29.927
−24.523
95.489
1.00
22.78
ATOM
2021
C
THR
450
33.108
−24.109
93.368
1.00
24.60
ATOM
2022
O
THR
450
33.469
−25.248
93.088
1.00
23.80
ATOM
2023
N
GLY
451
33.542
−23.042
92.718
1.00
25.04
ATOM
2024
CA
GLY
451
34.470
−23.200
91.620
1.00
26.73
ATOM
2025
C
GLY
451
34.924
−21.855
91.118
1.00
26.65
ATOM
2026
O
GLY
451
34.370
−20.828
91.505
1.00
27.30
ATOM
2027
N
LEU
452
35.945
−21.851
90.273
1.00
26.29
ATOM
2028
CA
LEU
452
36.439
−20.592
89.739
1.00
27.72
ATOM
2029
CB
LEU
452
37.798
−20.211
90.351
1.00
25.03
ATOM
2030
CG
LEU
452
37.865
−19.937
91.850
1.00
23.22
ATOM
2031
CD1
LEU
452
37.792
−21.248
92.592
1.00
22.91
ATOM
2032
CD2
LEU
452
39.150
−19.225
92.198
1.00
22.12
ATOM
2033
C
LEU
452
36.602
−20.720
88.249
1.00
27.91
ATOM
2034
O
LEU
452
36.381
−21.784
87.678
1.00
30.44
ATOM
2035
N
LEU
453
36.983
−19.620
87.626
1.00
25.60
ATOM
2036
CA
LEU
453
37.223
−19.605
86.211
1.00
24.90
ATOM
2037
CB
LEU
453
36.071
−18.936
85.473
1.00
21.07
ATOM
2038
CG
LEU
453
34.724
−19.652
85.532
1.00
16.96
ATOM
2039
CD1
LEU
453
33.754
−18.930
84.649
1.00
17.51
ATOM
2040
CD2
LEU
453
34.850
−21.061
85.077
1.00
13.58
ATOM
2041
C
LEU
453
38.485
−18.790
86.124
1.00
27.06
ATOM
2042
O
LEU
453
38.458
−17.568
86.262
1.00
28.02
ATOM
2043
N
LEU
454
39.602
−19.480
85.936
1.00
28.63
ATOM
2044
CA
LEU
454
40.889
−18.809
85.862
1.00
30.83
ATOM
2045
CB
LEU
454
41.898
−19.483
86.789
1.00
29.19
ATOM
2046
CG
LEU
454
41.646
−19.667
88.277
1.00
28.21
ATOM
2047
CD1
LEU
454
42.802
−20.460
88.863
1.00
28.15
ATOM
2048
CD2
LEU
454
41.527
−18.331
88.961
1.00
28.25
ATOM
2049
C
LEU
454
41.474
−18.815
84.465
1.00
32.86
ATOM
2050
O
LEU
454
41.103
−19.631
83.622
1.00
33.87
ATOM
2051
N
THR
455
42.415
−17.904
84.248
1.00
34.41
ATOM
2052
CA
THR
455
43.123
−17.791
82.984
1.00
37.13
ATOM
2053
CB
THR
455
42.759
−16.519
82.250
1.00
38.41
ATOM
2054
OG1
THR
455
41.340
−16.467
82.075
1.00
41.71
ATOM
2055
CG2
THR
455
43.438
−16.491
80.893
1.00
38.74
ATOM
2056
C
THR
455
44.591
−17.716
83.344
1.00
38.29
ATOM
2057
O
THR
455
44.943
−17.138
84.367
1.00
38.34
ATOM
2058
N
ARG
456
45.450
−18.289
82.508
1.00
39.99
ATOM
2059
CA
ARG
456
46.881
−18.277
82.783
1.00
41.61
ATOM
2060
CB
ARG
456
47.424
−19.698
82.719
1.00
42.00
ATOM
2061
CG
ARG
456
48.889
−19.811
83.063
1.00
44.96
ATOM
2062
CD
ARG
456
49.323
−21.250
82.973
1.00
47.06
ATOM
2063
NE
ARG
456
49.147
−21.774
81.621
1.00
49.39
ATOM
2064
CZ
ARG
456
50.117
−21.842
80.714
1.00
50.82
ATOM
2065
NH1
ARG
456
49.857
−22.331
79.506
1.00
52.13
ATOM
2066
NH2
ARG
456
51.348
−21.439
81.019
1.00
49.94
ATOM
2067
C
ARG
456
47.664
−17.389
81.825
1.00
42.48
ATOM
2068
O
ARG
456
47.665
−17.626
80.624
1.00
41.96
ATOM
2069
N
ASP
457
48.333
−16.371
82.362
1.00
44.50
ATOM
2070
CA
ASP
457
49.124
−15.451
81.541
1.00
46.62
ATOM
2071
CB
ASP
457
49.969
−14.515
82.414
1.00
45.79
ATOM
2072
CG
ASP
457
49.169
−13.352
82.978
1.00
46.16
ATOM
2073
OD1
ASP
457
49.798
−12.434
83.549
1.00
44.86
ATOM
2074
OD2
ASP
457
47.921
−13.355
82.853
1.00
44.91
ATOM
2075
C
ASP
457
50.051
−16.199
80.597
1.00
48.50
ATOM
2076
O
ASP
457
49.941
−16.088
79.378
1.00
48.45
ATOM
2077
N
GLY
458
50.975
−16.959
81.168
1.00
51.31
ATOM
2078
CA
GLY
458
51.898
−17.712
80.346
1.00
54.51
ATOM
2079
C
GLY
458
52.751
−16.795
79.499
1.00
57.29
ATOM
2080
O
GLY
458
53.043
−15.659
79.886
1.00
56.35
ATOM
2081
N
GLY
459
53.145
−17.288
78.332
1.00
60.01
ATOM
2082
CA
GLY
459
53.980
−16.494
77.454
1.00
63.76
ATOM
2083
C
GLY
459
55.443
−16.727
77.769
1.00
66.68
ATOM
2084
O
GLY
459
55.830
−16.889
78.932
1.00
66.19
ATOM
2085
N
ASN
460
56.254
−16.735
76.716
1.00
69.80
ATOM
2086
CA
ASN
460
57.694
−16.954
76.813
1.00
73.18
ATOM
2087
CB
ASN
460
58.357
−16.575
75.486
1.00
73.04
ATOM
2088
CG
ASN
460
57.866
−17.426
74.325
1.00
73.09
ATOM
2089
OD1
ASN
460
56.884
−18.161
74.450
1.00
73.18
ATOM
2090
ND2
ASN
460
58.543
−17.323
73.186
1.00
72.64
ATOM
2091
C
ASN
460
58.409
−16.242
77.965
1.00
75.44
ATOM
2092
O
ASN
460
58.412
−15.010
78.062
1.00
75.19
ATOM
2093
N
SER
461
59.021
−17.051
78.828
1.00
77.97
ATOM
2094
CA
SER
461
59.771
−16.582
79.987
1.00
80.75
ATOM
2095
CB
SER
461
58.858
−15.820
80.955
1.00
80.97
ATOM
2096
OG
SER
461
59.608
−15.227
82.007
1.00
81.02
ATOM
2097
C
SER
461
60.368
−17.804
80.689
1.00
82.74
ATOM
2098
O
SER
461
59.649
−18.579
81.332
1.00
82.67
ATOM
2099
N
ASN
462
61.682
−17.979
80.545
1.00
84.51
ATOM
2100
CA
ASN
462
62.399
−19.101
81.160
1.00
85.75
ATOM
2101
CB
ASN
462
63.877
−19.043
80.770
1.00
86.14
ATOM
2102
CG
ASN
462
64.408
−17.626
80.735
1.00
86.77
ATOM
2103
OD1
ASN
462
64.320
−16.891
81.723
1.00
87.52
ATOM
2104
ND2
ASN
462
64.963
−17.230
79.594
1.00
86.09
ATOM
2105
C
ASN
462
62.248
−19.078
82.681
1.00
85.99
ATOM
2106
O
ASN
462
62.664
−20.014
83.377
1.00
86.05
ATOM
2107
N
ASN
463
61.648
−17.992
83.172
1.00
85.36
ATOM
2108
CA
ASN
463
61.379
−17.775
84.591
1.00
84.11
ATOM
2109
CB
ASN
463
60.737
−16.395
84.774
1.00
86.07
ATOM
2110
CG
ASN
463
60.656
−15.967
86.227
1.00
88.02
ATOM
2111
OD1
ASN
463
60.296
−16.757
87.101
1.00
90.17
ATOM
2112
ND2
ASN
463
60.976
−14.703
86.490
1.00
88.10
ATOM
2113
C
ASN
463
60.392
−18.861
85.012
1.00
82.29
ATOM
2114
O
ASN
463
59.372
−19.058
84.351
1.00
82.70
ATOM
2115
N
GLU
464
60.684
−19.569
86.098
1.00
79.57
ATOM
2116
CA
GLU
464
59.788
−20.631
86.542
1.00
76.54
ATOM
2117
CB
GLU
464
60.598
−21.833
87.058
1.00
79.45
ATOM
2118
CG
GLU
464
61.323
−22.608
85.943
1.00
82.50
ATOM
2119
CD
GLU
464
62.120
−23.814
86.448
1.00
85.16
ATOM
2120
OE1
GLU
464
62.812
−24.457
85.620
1.00
85.88
ATOM
2121
OE2
GLU
464
62.055
−24.121
87.663
1.00
85.82
ATOM
2122
C
GLU
464
58.765
−20.185
87.583
1.00
72.60
ATOM
2123
O
GLU
464
58.986
−20.303
88.788
1.00
71.55
ATOM
2124
N
SER
465
57.639
−19.677
87.081
1.00
68.78
ATOM
2125
CA
SER
465
56.516
−19.200
87.893
1.00
64.10
ATOM
2126
CB
SER
465
56.918
−17.974
88.715
1.00
63.31
ATOM
2127
OG
SER
465
57.130
−16.853
87.880
1.00
60.85
ATOM
2128
C
SER
465
55.356
−18.818
86.968
1.00
60.87
ATOM
2129
O
SER
465
55.526
−18.016
86.049
1.00
59.72
ATOM
2130
N
GLU
466
54.184
−19.397
87.215
1.00
57.26
ATOM
2131
CA
GLU
466
52.994
−19.126
86.410
1.00
53.95
ATOM
2132
CB
GLU
466
52.200
−20.413
86.211
1.00
54.65
ATOM
2133
CG
GLU
466
52.956
−21.470
85.438
1.00
56.85
ATOM
2134
CD
GLU
466
53.221
−21.049
84.011
1.00
57.73
ATOM
2135
OE1
GLU
466
54.153
−21.608
83.395
1.00
58.80
ATOM
2136
OE2
GLU
466
52.492
−20.165
83.506
1.00
57.31
ATOM
2137
C
GLU
466
52.110
−18.087
87.080
1.00
51.49
ATOM
2138
O
GLU
466
52.057
−18.015
88.306
1.00
51.94
ATOM
2139
N
ILE
467
51.419
−17.276
86.283
1.00
47.68
ATOM
2140
CA
ILE
467
50.543
−16.254
86.850
1.00
44.16
ATOM
2141
CB
ILE
467
50.903
−14.837
86.354
1.00
42.54
ATOM
2142
CG2
ILE
467
50.189
−13.805
87.209
1.00
41.04
ATOM
2143
CG1
ILE
467
52.410
−14.601
86.454
1.00
41.74
ATOM
2144
CD1
ILE
467
52.829
−13.208
86.044
1.00
40.72
ATOM
2145
C
ILE
467
49.100
−16.539
86.466
1.00
42.71
ATOM
2146
O
ILE
467
48.817
−16.864
85.315
1.00
43.08
ATOM
2147
N
PHE
468
48.187
−16.421
87.423
1.00
39.98
ATOM
2148
CA
PHE
468
46.793
−16.684
87.129
1.00
38.70
ATOM
2149
CB
PHE
468
46.347
−17.953
87.827
1.00
39.01
ATOM
2150
CG
PHE
468
47.216
−19.127
87.541
1.00
40.09
ATOM
2151
CD1
PHE
468
48.465
−19.243
88.145
1.00
40.16
ATOM
2152
CD2
PHE
468
46.789
−20.127
86.670
1.00
41.47
ATOM
2153
CE1
PHE
468
49.280
−20.334
87.891
1.00
40.98
ATOM
2154
CE2
PHE
468
47.596
−21.229
86.404
1.00
42.44
ATOM
2155
CZ
PHE
468
48.847
−21.333
87.018
1.00
42.97
ATOM
2156
C
PHE
468
45.863
−15.552
87.515
1.00
38.30
ATOM
2157
O
PHE
468
46.022
−14.928
88.563
1.00
39.47
ATOM
2158
N
ARG
469
44.876
−15.305
86.664
1.00
36.77
ATOM
2159
CA
ARG
469
43.912
−14.250
86.897
1.00
35.74
ATOM
2160
CB
ARG
469
44.139
−13.121
85.907
1.00
34.66
ATOM
2161
CG
ARG
469
45.560
−12.642
85.831
1.00
33.62
ATOM
2162
CD
ARG
469
45.735
−11.760
84.620
1.00
33.99
ATOM
2163
NE
ARG
469
47.111
−11.330
84.426
1.00
32.62
ATOM
2164
CZ
ARG
469
47.721
−10.426
85.179
1.00
32.46
ATOM
2165
NH1
ARG
469
47.083
−9.851
86.182
1.00
32.30
ATOM
2166
NH2
ARG
469
48.968
−10.089
84.918
1.00
33.90
ATOM
2167
C
ARG
469
42.522
−14.811
86.690
1.00
35.90
ATOM
2168
O
ARG
469
42.344
−15.782
85.968
1.00
37.30
ATOM
2169
N
PRO
470
41.512
−14.196
87.316
1.00
36.11
ATOM
2170
CD
PRO
470
41.626
−13.004
88.173
1.00
37.74
ATOM
2171
CA
PRO
470
40.117
−14.628
87.205
1.00
35.55
ATOM
2172
CB
PRO
470
39.425
−13.835
88.306
1.00
37.42
ATOM
2173
CG
PRO
470
40.181
−12.546
88.299
1.00
37.79
ATOM
2174
C
PRO
470
39.572
−14.304
85.826
1.00
34.84
ATOM
2175
O
PRO
470
39.664
−13.163
85.350
1.00
32.79
ATOM
2176
N
GLY
471
39.009
−15.318
85.182
1.00
34.39
ATOM
2177
CA
GLY
471
38.481
−15.126
83.849
1.00
34.12
ATOM
2178
C
GLY
471
37.014
−15.447
83.762
1.00
33.66
ATOM
2179
O
GLY
471
36.250
−15.157
84.681
1.00
32.21
ATOM
2180
N
GLY
472
36.630
−16.054
82.646
1.00
34.79
ATOM
2181
CA
GLY
472
35.242
−16.408
82.433
1.00
36.19
ATOM
2182
C
GLY
472
34.526
−15.361
81.600
1.00
37.07
ATOM
2183
O
GLY
472
35.141
−14.417
81.090
1.00
37.63
ATOM
2184
N
GLY
473
33.218
−15.516
81.471
1.00
36.43
ATOM
2185
CA
GLY
473
32.451
−14.578
80.687
1.00
36.25
ATOM
2186
C
GLY
473
31.703
−15.393
79.669
1.00
37.28
ATOM
2187
O
GLY
473
30.653
−14.982
79.179
1.00
37.79
ATOM
2188
N
ASP
474
32.253
−16.562
79.351
1.00
37.46
ATOM
2189
CA
ASP
474
31.620
−17.455
78.396
1.00
38.13
ATOM
2190
CB
ASP
474
32.666
−18.142
77.528
1.00
39.46
ATOM
2191
CG
ASP
474
32.042
−18.956
76.420
1.00
41.78
ATOM
2192
OD1
ASP
474
30.863
−19.345
76.567
1.00
41.80
ATOM
2193
OD2
ASP
474
32.726
−19.215
75.408
1.00
43.88
ATOM
2194
C
ASP
474
30.842
−18.501
79.179
1.00
37.74
ATOM
2195
O
ASP
474
31.350
−19.584
79.445
1.00
38.81
ATOM
2196
N
MET
475
29.609
−18.166
79.543
1.00
37.28
ATOM
2197
CA
MET
475
28.741
−19.049
80.318
1.00
36.81
ATOM
2198
CB
MET
475
27.297
−18.559
80.213
1.00
36.74
ATOM
2199
CG
MET
475
26.718
−18.082
81.529
1.00
37.69
ATOM
2200
SD
MET
475
27.926
−17.234
82.557
1.00
38.71
ATOM
2201
CE
MET
475
28.119
−15.706
81.638
1.00
38.89
ATOM
2202
C
MET
475
28.814
−20.542
79.979
1.00
37.19
ATOM
2203
O
MET
475
28.382
−21.382
80.773
1.00
37.30
ATOM
2204
N
ARG
476
29.353
−20.878
78.809
1.00
36.64
ATOM
2205
CA
ARG
476
29.484
−22.273
78.420
1.00
34.96
ATOM
2206
CB
ARG
476
29.919
−22.392
76.973
1.00
37.33
ATOM
2207
CG
ARG
476
28.879
−21.935
75.991
1.00
39.91
ATOM
2208
CD
ARG
476
29.264
−22.348
74.595
1.00
43.35
ATOM
2209
NE
ARG
476
28.644
−21.475
73.610
1.00
48.16
ATOM
2210
CZ
ARG
476
29.072
−20.246
73.339
1.00
50.83
ATOM
2211
NH1
ARG
476
30.130
−19.751
73.978
1.00
50.44
ATOM
2212
NH2
ARG
476
28.434
−19.508
72.438
1.00
52.09
ATOM
2213
C
ARG
476
30.505
−22.950
79.309
1.00
34.15
ATOM
2214
O
ARG
476
30.466
−24.155
79.495
1.00
33.39
ATOM
2215
N
ASP
477
31.437
−22.175
79.846
1.00
33.97
ATOM
2216
CA
ASP
477
32.428
−22.731
80.748
1.00
34.21
ATOM
2217
CB
ASP
477
33.497
−21.702
81.091
1.00
34.12
ATOM
2218
CG
ASP
477
34.475
−21.478
79.971
1.00
35.39
ATOM
2219
OD1
ASP
477
34.800
−22.449
79.256
1.00
36.22
ATOM
2220
OD2
ASP
477
34.937
−20.326
79.823
1.00
37.07
ATOM
2221
C
ASP
477
31.696
−23.120
82.030
1.00
35.79
ATOM
2222
O
ASP
477
31.977
−24.157
82.640
1.00
36.61
ATOM
2223
N
ASN
478
30.753
−22.278
82.440
1.00
35.81
ATOM
2224
CA
ASN
478
29.992
−22.539
83.647
1.00
35.64
ATOM
2225
CB
ASN
478
29.160
−21.315
84.029
1.00
37.76
ATOM
2226
CG
ASN
478
29.987
−20.040
84.081
1.00
39.41
ATOM
2227
OD1
ASN
478
29.613
−19.070
84.748
1.00
40.06
ATOM
2228
ND2
ASN
478
31.108
−20.029
83.363
1.00
37.85
ATOM
2229
C
ASN
478
29.096
−23.756
83.478
1.00
34.88
ATOM
2230
O
ASN
478
28.958
−24.550
84.389
1.00
34.09
ATOM
2231
N
TRP
479
28.479
−23.906
82.316
1.00
34.86
ATOM
2232
CA
TRP
479
27.641
−25.070
82.078
1.00
36.03
ATOM
2233
CB
TRP
479
26.892
−24.932
80.760
1.00
37.78
ATOM
2234
CG
TRP
479
26.218
−23.624
80.555
1.00
40.26
ATOM
2235
CD2
TRP
479
25.541
−22.847
81.536
1.00
40.78
ATOM
2236
CE2
TRP
479
25.028
−21.702
80.883
1.00
41.01
ATOM
2237
CE3
TRP
479
25.314
−23.002
82.904
1.00
41.79
ATOM
2238
CD1
TRP
479
26.095
−22.943
79.374
1.00
41.62
ATOM
2239
NE1
TRP
479
25.380
−21.787
79.562
1.00
41.25
ATOM
2240
CZ2
TRP
479
24.307
−20.719
81.552
1.00
40.72
ATOM
2241
CZ3
TRP
479
24.595
−22.023
83.569
1.00
43.55
ATOM
2242
CH2
TRP
479
24.099
−20.894
82.889
1.00
42.51
ATOM
2243
C
TRP
479
28.576
−26.270
81.972
1.00
35.96
ATOM
2244
O
TRP
479
28.297
−27.346
82.476
1.00
37.65
ATOM
2245
N
ARG
480
29.700
−26.070
81.304
1.00
36.48
ATOM
2246
CA
ARG
480
30.685
−27.126
81.108
1.00
37.20
ATOM
2247
CB
ARG
480
31.863
−26.576
80.284
1.00
39.00
ATOM
2248
CG
ARG
480
32.614
−27.615
79.462
1.00
40.70
ATOM
2249
CD
ARG
480
33.888
−27.058
78.807
1.00
42.07
ATOM
2250
NE
ARG
480
33.624
−25.883
77.995
1.00
41.84
ATOM
2251
CZ
ARG
480
32.745
−25.850
77.002
1.00
41.61
ATOM
2252
NH1
ARG
480
32.044
−26.937
76.691
1.00
41.31
ATOM
2253
NH2
ARG
480
32.552
−24.720
76.337
1.00
41.06
ATOM
2254
C
ARG
480
31.202
−27.706
82.428
1.00
36.72
ATOM
2255
O
ARG
480
31.560
−28.869
82.495
1.00
37.82
ATOM
2256
N
SER
481
31.236
−26.899
83.479
1.00
36.72
ATOM
2257
CA
SER
481
31.738
−27.367
84.765
1.00
37.00
ATOM
2258
CB
SER
481
32.088
−26.182
85.645
1.00
36.50
ATOM
2259
OG
SER
481
30.897
−25.619
86.144
1.00
33.89
ATOM
2260
C
SER
481
30.742
−28.243
85.516
1.00
37.55
ATOM
2261
O
SER
481
31.024
−28.717
86.616
1.00
36.47
ATOM
2262
N
GLU
482
29.575
−28.453
84.933
1.00
38.59
ATOM
2263
CA
GLU
482
28.572
−29.269
85.583
1.00
40.68
ATOM
2264
CB
GLU
482
27.350
−28.418
85.922
1.00
42.64
ATOM
2265
CG
GLU
482
27.521
−27.504
87.131
1.00
44.81
ATOM
2266
CD
GLU
482
26.957
−28.100
88.412
1.00
46.18
ATOM
2267
OE1
GLU
482
25.726
−28.318
88.481
1.00
47.32
ATOM
2268
OE2
GLU
482
27.744
−28.348
89.353
1.00
46.06
ATOM
2269
C
GLU
482
28.163
−30.428
84.697
1.00
41.36
ATOM
2270
O
GLU
482
27.733
−31.472
85.188
1.00
43.64
ATOM
2271
N
LEU
483
28.304
−30.255
83.391
1.00
40.45
ATOM
2272
CA
LEU
483
27.919
−31.303
82.459
1.00
40.92
ATOM
2273
CB
LEU
483
27.182
−30.673
81.283
1.00
40.20
ATOM
2274
CG
LEU
483
25.928
−29.921
81.723
1.00
40.80
ATOM
2275
CD1
LEU
483
25.420
−29.072
80.587
1.00
41.63
ATOM
2276
CD2
LEU
483
24.874
−30.909
82.175
1.00
41.17
ATOM
2277
C
LEU
483
29.096
−32.132
81.951
1.00
41.69
ATOM
2278
O
LEU
483
28.931
−33.000
81.092
1.00
41.28
ATOM
2279
N
TYR
484
30.282
−31.880
82.492
1.00
41.67
ATOM
2280
CA
TYR
484
31.463
−32.598
82.050
1.00
42.77
ATOM
2281
CB
TYR
484
32.684
−32.103
82.830
1.00
42.89
ATOM
2282
CG
TYR
484
32.695
−32.515
84.277
1.00
43.93
ATOM
2283
CD1
TYR
484
33.244
−33.735
84.668
1.00
44.09
ATOM
2284
CE1
TYR
484
33.210
−34.148
86.000
1.00
43.91
ATOM
2285
CD2
TYR
484
32.113
−31.714
85.255
1.00
43.24
ATOM
2286
CE2
TYR
484
32.074
−32.121
86.588
1.00
42.95
ATOM
2287
CZ
TYR
484
32.624
−33.337
86.950
1.00
42.55
ATOM
2288
OH
TYR
484
32.605
−33.739
88.263
1.00
43.56
ATOM
2289
C
TYR
484
31.316
−34.120
82.176
1.00
43.44
ATOM
2290
O
TYR
484
31.810
−34.877
81.327
1.00
42.64
ATOM
2291
N
LYS
485
30.622
−34.562
83.221
1.00
43.25
ATOM
2292
CA
LYS
485
30.424
−35.989
83.449
1.00
44.97
ATOM
2293
CB
LYS
485
30.249
−36.265
84.946
1.00
46.94
ATOM
2294
CG
LYS
485
29.083
−35.540
85.606
1.00
49.26
ATOM
2295
CD
LYS
485
29.109
−35.779
87.115
1.00
53.35
ATOM
2296
CE
LYS
485
28.091
−34.913
87.862
1.00
55.98
ATOM
2297
NZ
LYS
485
28.190
−35.067
89.350
1.00
55.85
ATOM
2298
C
LYS
485
29.230
−36.557
82.686
1.00
44.79
ATOM
2299
O
LYS
485
28.637
−37.547
83.105
1.00
45.03
ATOM
2300
N
TYR
486
28.876
−35.931
81.568
1.00
43.62
ATOM
2301
CA
TYR
486
27.750
−36.389
80.767
1.00
41.82
ATOM
2302
CB
TYR
486
26.523
−35.492
80.970
1.00
38.82
ATOM
2303
CG
TYR
486
25.915
−35.521
82.350
1.00
36.43
ATOM
2304
CD1
TYR
486
26.240
−34.550
83.299
1.00
37.04
ATOM
2305
CE1
TYR
486
25.677
−34.577
84.576
1.00
36.71
ATOM
2306
CD2
TYR
486
25.011
−36.514
82.709
1.00
34.16
ATOM
2307
CE2
TYR
486
24.445
−36.550
83.979
1.00
33.33
ATOM
2308
CZ
TYR
486
24.777
−35.583
84.904
1.00
34.49
ATOM
2309
OH
TYR
486
24.220
−35.624
86.158
1.00
34.00
ATOM
2310
C
TYR
486
28.089
−36.382
79.291
1.00
42.66
ATOM
2311
O
TYR
486
29.078
−35.796
78.866
1.00
44.53
ATOM
2312
N
LYS
487
27.249
−37.041
78.509
1.00
43.23
ATOM
2313
CA
LYS
487
27.413
−37.090
77.070
1.00
43.39
ATOM
2314
CB
LYS
487
28.638
−37.915
76.670
1.00
42.59
ATOM
2315
CG
LYS
487
28.399
−39.401
76.615
1.00
42.82
ATOM
2316
CD
LYS
487
29.518
−40.088
75.855
1.00
45.58
ATOM
2317
CE
LYS
487
29.612
−39.594
74.405
1.00
46.48
ATOM
2318
NZ
LYS
487
30.745
−40.213
73.638
1.00
44.44
ATOM
2319
C
LYS
487
26.149
−37.724
76.527
1.00
43.48
ATOM
2320
O
LYS
487
25.597
−38.640
77.128
1.00
43.29
ATOM
2321
N
VAL
488
25.682
−37.217
75.400
1.00
44.12
ATOM
2322
CA
VAL
488
24.475
−37.729
74.790
1.00
45.91
ATOM
2323
CB
VAL
488
23.558
−36.554
74.409
1.00
44.11
ATOM
2324
CG1
VAL
488
24.209
−35.720
73.338
1.00
44.27
ATOM
2325
CG2
VAL
488
22.214
−37.056
73.966
1.00
44.39
ATOM
2326
C
VAL
488
24.864
−38.554
73.557
1.00
48.36
ATOM
2327
O
VAL
488
25.888
−38.290
72.927
1.00
48.88
ATOM
2328
N
VAL
489
24.070
−39.570
73.223
1.00
51.09
ATOM
2329
CA
VAL
489
24.383
−40.403
72.060
1.00
53.62
ATOM
2330
CB
VAL
489
25.341
−41.573
72.438
1.00
53.16
ATOM
2331
CG1
VAL
489
24.659
−42.513
73.409
1.00
51.07
ATOM
2332
CG2
VAL
489
25.783
−42.316
71.178
1.00
52.29
ATOM
2333
C
VAL
489
23.161
−40.983
71.344
1.00
55.28
ATOM
2334
O
VAL
489
22.115
−41.249
71.956
1.00
55.15
ATOM
2335
N
LYS
490
23.317
−41.163
70.033
1.00
56.80
ATOM
2336
CA
LYS
490
22.272
−41.708
69.179
1.00
58.05
ATOM
2337
CB
LYS
490
22.757
−41.833
67.729
1.00
59.78
ATOM
2338
CG
LYS
490
23.172
−40.539
67.031
1.00
63.37
ATOM
2339
CD
LYS
490
24.493
−39.974
67.570
1.00
66.32
ATOM
2340
CE
LYS
490
25.132
−38.975
66.597
1.00
66.85
ATOM
2341
NZ
LYS
490
24.183
−37.926
66.111
1.00
68.56
ATOM
2342
C
LYS
490
21.928
−43.094
69.671
1.00
57.96
ATOM
2343
O
LYS
490
22.825
−43.917
69.873
1.00
58.39
ATOM
2344
N
ILE
491
20.642
−43.364
69.868
1.00
57.59
ATOM
2345
CA
ILE
491
20.237
−44.697
70.303
1.00
56.42
ATOM
2346
CB
ILE
491
18.861
−44.685
70.982
1.00
53.57
ATOM
2347
CG2
ILE
491
18.641
−45.994
71.698
1.00
52.55
ATOM
2348
CG1
ILE
491
18.776
−43.545
71.983
1.00
52.06
ATOM
2349
CD1
ILE
491
17.409
−43.403
72.594
1.00
50.94
ATOM
2350
C
ILE
491
20.144
−45.570
69.045
1.00
57.42
ATOM
2351
O
ILE
491
19.728
−45.038
67.989
1.00
57.28
ATOM
2352
OXT
ILE
491
20.478
−46.769
69.127
1.00
58.91
END
VII. Crystals of gp120 with an Extended V3 Loop
The present disclosure further relates to the crystal structure of gp120 in which the V3 loop is in an extended conformation. The present disclosure also relates to the crystals obtained from a gp120 polypeptide with an extended V3 loop. The three-dimensional coordinates of a gp120 polypeptide with an extended V3 loop, three-dimensional structures of models of a gp120 polypeptide with an extended V3 loop, and uses of these models. The amino acid sequence of a gp120 polypeptide with an extended V3 loop variant is set forth as SEQ ID NO: 2.
The structure of a gp120 polypeptide with an extended V3 loop was solved in complex with the X5 Fab and the d1d2 domain of the CD4 receptor. Analysis of the structure revealed that the V3 loop was present in an elongated conformation that was previously not seen in other complexes involving the gp120 protein. An advantageous feature of this crystal structure over previous structures is the organization of the V3 loop in an elongated conformation, compatible with the elicitation of immunodominant antibody response. Table 2 provides the atomic coordinates of the crystal structure of the polypeptide disclosed in SEQ ID NO: 2.
TABLE 2
The structural coordinates of an exemplary gp120 with an extended V3 loop
ATOM
1
N
VAL
G
84
83.090
−158.764
98.727
1.00
133.29
ATOM
2
CA
VAL
G
84
84.569
−158.842
98.897
1.00
133.95
ATOM
3
C
VAL
G
84
85.258
−158.165
97.714
1.00
134.16
ATOM
4
O
VAL
G
84
85.855
−158.828
96.866
1.00
134.41
ATOM
5
CB
VAL
G
84
85.039
−160.312
98.978
1.00
134.07
ATOM
6
CG1
VAL
G
84
86.507
−160.372
99.373
1.00
134.72
ATOM
7
CG2
VAL
G
84
84.181
−161.078
99.974
1.00
132.76
ATOM
8
N
VAL
G
85
85.169
−156.839
97.667
1.00
134.17
ATOM
9
CA
VAL
G
85
85.767
−156.061
96.587
1.00
133.97
ATOM
10
C
VAL
G
85
87.243
−155.768
96.832
1.00
134.16
ATOM
11
O
VAL
G
85
87.711
−155.788
97.971
1.00
134.47
ATOM
12
CB
VAL
G
85
85.026
−154.715
96.401
1.00
133.69
ATOM
13
CG1
VAL
G
85
85.141
−153.883
97.666
1.00
133.08
ATOM
14
CG2
VAL
G
85
85.601
−153.958
95.213
1.00
133.51
ATOM
15
N
LEU
G
86
87.971
−155.505
95.751
1.00
134.10
ATOM
16
CA
LEU
G
86
89.392
−155.192
95.827
1.00
134.30
ATOM
17
C
LEU
G
86
89.724
−154.045
94.874
1.00
134.27
ATOM
18
O
LEU
G
86
90.077
−154.264
93.714
1.00
134.21
ATOM
19
CB
LEU
G
86
90.235
−156.426
95.483
1.00
134.49
ATOM
20
CG
LEU
G
86
90.134
−157.616
96.446
1.00
134.44
ATOM
21
CD1
LEU
G
86
88.803
−158.331
96.264
1.00
134.35
ATOM
22
CD2
LEU
G
86
91.277
−158.581
96.183
1.00
134.28
ATOM
23
N
GLU
G
87
89.663
−152.780
95.269
1.00
136.00
ATOM
24
CA
GLU
G
87
89.975
−151.658
94.374
1.00
136.69
ATOM
25
C
GLU
G
87
91.472
−151.398
94.342
1.00
137.59
ATOM
26
O
GLU
G
87
92.122
−151.341
95.383
1.00
138.06
ATOM
27
CB
GLU
G
87
89.285
−150.383
94.827
1.00
135.94
ATOM
28
CG
GLU
G
87
87.799
−150.526
94.988
1.00
136.55
ATOM
29
CD
GLU
G
87
87.274
−149.713
96.220
1.00
137.15
ATOM
30
OE1
GLU
G
87
88.011
−149.739
97.285
1.00
138.80
ATOM
31
OE2
GLU
G
87
86.143
−149.072
96.141
1.00
137.57
ATOM
32
N
ASN
G
88
91.857
−151.247
93.247
1.00
136.70
ATOM
33
CA
ASN
G
88
93.272
−150.981
92.995
1.00
137.44
ATOM
34
C
ASN
G
88
93.532
−149.487
92.827
1.00
138.14
ATOM
35
O
ASN
G
88
93.615
−148.984
91.707
1.00
138.46
ATOM
36
CB
ASN
G
88
93.735
−151.732
91.741
1.00
137.16
ATOM
37
CG
ASN
G
88
95.046
−151.199
91.192
1.00
137.46
ATOM
38
OD1
ASN
G
88
96.022
−151.042
91.924
1.00
137.34
ATOM
39
ND2
ASN
G
88
95.074
−150.921
89.892
1.00
138.00
ATOM
40
N
VAL
G
89
93.664
−148.778
93.944
1.00
138.65
ATOM
41
CA
VAL
G
89
93.906
−147.342
93.893
1.00
138.82
ATOM
42
C
VAL
G
89
94.756
−146.842
95.059
1.00
139.51
ATOM
43
O
VAL
G
89
94.835
−147.483
96.108
1.00
139.82
ATOM
44
CB
VAL
G
89
92.570
−146.564
93.877
1.00
138.22
ATOM
45
CG1
VAL
G
89
91.797
−146.834
95.158
1.00
137.56
ATOM
46
CG2
VAL
G
89
92.830
−145.076
93.703
1.00
137.89
ATOM
47
N
THR
G
90
95.394
−145.693
94.856
1.00
139.18
ATOM
48
CA
THR
G
90
96.233
−145.076
95.874
1.00
138.77
ATOM
49
C
THR
G
90
95.355
−144.357
96.903
1.00
137.61
ATOM
50
O
THR
G
90
94.887
−143.241
96.671
1.00
137.17
ATOM
51
CB
THR
G
90
97.224
−144.075
95.229
1.00
139.07
ATOM
52
OG1
THR
G
90
97.906
−143.340
96.252
1.00
139.89
ATOM
53
CG2
THR
G
90
96.490
−143.113
94.303
1.00
138.94
ATOM
54
N
GLU
G
91
95.133
−145.015
98.038
1.00
136.88
ATOM
55
CA
GLU
G
91
94.302
−144.480
99.117
1.00
136.34
ATOM
56
C
GLU
G
91
94.989
−143.439
99.999
1.00
136.12
ATOM
57
O
GLU
G
91
95.991
−143.730
100.653
1.00
136.07
ATOM
58
CB
GLU
G
91
93.806
−145.627
100.002
1.00
135.71
ATOM
59
CG
GLU
G
91
92.609
−146.385
99.457
1.00
134.03
ATOM
60
CD
GLU
G
91
91.293
−145.844
99.980
1.00
132.56
ATOM
61
OE1
GLU
G
91
90.982
−144.661
99.725
1.00
131.44
ATOM
62
OE2
GLU
G
91
90.568
−146.606
100.653
1.00
131.61
ATOM
63
N
HIS
G
92
94.430
−142.231
100.027
1.00
135.50
ATOM
64
CA
HIS
G
92
94.973
−141.145
100.838
1.00
134.96
ATOM
65
C
HIS
G
92
94.490
−141.268
102.282
1.00
133.04
ATOM
66
O
HIS
G
92
93.411
−141.798
102.537
1.00
133.15
ATOM
67
CB
HIS
G
92
94.541
−139.793
100.266
1.00
138.44
ATOM
68
CG
HIS
G
92
95.064
−139.522
98.889
1.00
142.66
ATOM
69
ND1
HIS
G
92
94.870
−138.319
98.245
1.00
144.46
ATOM
70
CD2
HIS
G
92
95.775
−140.296
98.035
1.00
143.67
ATOM
71
CE1
HIS
G
92
95.441
−138.362
97.054
1.00
145.80
ATOM
72
NE2
HIS
G
92
95.997
−139.551
96.902
1.00
145.38
ATOM
73
N
PHE
G
93
95.289
−140.768
103.221
1.00
130.39
ATOM
74
CA
PHE
G
93
94.950
−140.836
104.640
1.00
126.69
ATOM
75
C
PHE
G
93
95.478
−139.628
105.413
1.00
125.30
ATOM
76
O
PHE
G
93
96.479
−139.026
105.033
1.00
125.23
ATOM
77
CB
PHE
G
93
95.534
−142.115
105.247
1.00
125.14
ATOM
78
CG
PHE
G
93
94.502
−143.095
105.721
1.00
123.03
ATOM
79
CD1
PHE
G
93
93.494
−143.538
104.871
1.00
122.34
ATOM
80
CD2
PHE
G
93
94.558
−143.600
107.013
1.00
122.41
ATOM
81
CE1
PHE
G
93
92.556
−144.470
105.304
1.00
121.87
ATOM
82
CE2
PHE
G
93
93.626
−144.532
107.456
1.00
121.75
ATOM
83
CZ
PHE
G
93
92.623
−144.969
106.599
1.00
121.40
ATOM
84
N
ASN
G
94
94.800
−139.283
106.502
1.00
123.37
ATOM
85
CA
ASN
G
94
95.207
−138.158
107.336
1.00
121.13
ATOM
86
C
ASN
G
94
94.643
−138.370
108.735
1.00
120.97
ATOM
87
O
ASN
G
94
93.696
−139.136
108.918
1.00
121.62
ATOM
88
CB
ASN
G
94
94.677
−136.839
106.762
1.00
118.89
ATOM
89
CG
ASN
G
94
95.603
−135.670
107.034
1.00
116.56
ATOM
90
OD1
ASN
G
94
96.617
−135.501
106.358
1.00
115.47
ATOM
91
ND2
ASN
G
94
95.266
−134.863
108.033
1.00
115.47
ATOM
92
N
MET
G
95
95.217
−137.687
109.719
1.00
120.03
ATOM
93
CA
MET
G
95
94.754
−137.820
111.094
1.00
119.35
ATOM
94
C
MET
G
95
94.581
−136.459
111.751
1.00
118.97
ATOM
95
O
MET
G
95
93.918
−136.332
112.780
1.00
118.34
ATOM
96
CB
MET
G
95
95.750
−138.658
111.900
1.00
119.23
ATOM
97
CG
MET
G
95
97.163
−138.093
111.906
1.00
119.40
ATOM
98
SD
MET
G
95
98.323
−139.128
112.817
1.00
118.08
ATOM
99
CE
MET
G
95
98.176
−138.435
114.461
1.00
119.02
ATOM
100
N
TRP
G
96
95.175
−135.438
111.144
1.00
119.91
ATOM
101
CA
TRP
G
96
95.102
−134.087
111.683
1.00
121.52
ATOM
102
C
TRP
G
96
93.868
−133.346
111.184
1.00
123.34
ATOM
103
O
TRP
G
96
93.242
−132.601
111.935
1.00
123.67
ATOM
104
CB
TRP
G
96
96.371
−133.312
111.323
1.00
120.30
ATOM
105
CG
TRP
G
96
97.616
−134.122
111.530
1.00
119.93
ATOM
106
CD1
TRP
G
96
98.257
−134.889
110.599
1.00
119.95
ATOM
107
CD2
TRP
G
96
98.326
−134.309
112.761
1.00
119.57
ATOM
108
NE1
TRP
G
96
99.321
−135.544
111.174
1.00
119.53
ATOM
109
CE2
TRP
G
96
99.387
−135.204
112.498
1.00
119.10
ATOM
110
CE3
TRP
G
96
98.170
−133.805
114.058
1.00
119.39
ATOM
111
CZ2
TRP
G
96
100.285
−135.611
113.490
1.00
118.59
ATOM
112
CZ3
TRP
G
96
99.064
−134.210
115.043
1.00
117.94
ATOM
113
CH2
TRP
G
96
100.109
−135.103
114.751
1.00
117.96
ATOM
114
N
LYS
G
97
93.519
−133.549
109.919
1.00
125.13
ATOM
115
CA
LYS
G
97
92.338
−132.906
109.350
1.00
127.15
ATOM
116
C
LYS
G
97
91.243
−133.960
109.235
1.00
127.03
ATOM
117
O
LYS
G
97
90.591
−134.084
108.201
1.00
127.49
ATOM
118
CB
LYS
G
97
92.656
−132.324
107.965
1.00
128.56
ATOM
119
CG
LYS
G
97
92.419
−130.817
107.836
1.00
130.40
ATOM
120
CD
LYS
G
97
93.554
−129.998
108.449
1.00
131.70
ATOM
121
CE
LYS
G
97
94.673
−129.727
107.447
1.00
132.45
ATOM
122
NZ
LYS
G
97
94.251
−128.765
106.387
1.00
132.15
ATOM
123
N
ASN
G
98
91.056
−134.719
110.309
1.00
127.04
ATOM
124
CA
ASN
G
98
90.060
−135.781
110.347
1.00
127.06
ATOM
125
C
ASN
G
98
88.846
−135.370
111.174
1.00
126.76
ATOM
126
O
ASN
G
98
88.979
−134.956
112.325
1.00
127.98
ATOM
127
CB
ASN
G
98
90.692
−137.051
110.924
1.00
126.57
ATOM
128
CG
ASN
G
98
89.763
−138.242
110.877
1.00
125.98
ATOM
129
OD1
ASN
G
98
88.791
−138.254
110.124
1.00
126.75
ATOM
130
ND2
ASN
G
98
90.067
−139.262
111.670
1.00
125.44
ATOM
131
N
ASP
G
99
87.665
−135.494
110.580
1.00
125.41
ATOM
132
CA
ASP
G
99
86.426
−135.125
111.251
1.00
124.29
ATOM
133
C
ASP
G
99
86.042
−136.161
112.303
1.00
122.94
ATOM
134
O
ASP
G
99
85.313
−135.865
113.253
1.00
123.21
ATOM
135
CB
ASP
G
99
85.309
−134.984
110.213
1.00
125.07
ATOM
136
CG
ASP
G
99
84.039
−134.383
110.792
1.00
125.46
ATOM
137
OD1
ASP
G
99
83.255
−135.132
111.407
1.00
125.32
ATOM
138
OD2
ASP
G
99
83.839
−133.158
110.637
1.00
125.35
ATOM
139
N
MET
G
100
86.548
−137.376
112.128
1.00
121.29
ATOM
140
CA
MET
G
100
86.264
−138.472
113.044
1.00
120.02
ATOM
141
C
MET
G
100
86.815
−138.176
114.432
1.00
119.25
ATOM
142
O
MET
G
100
86.282
−138.649
115.436
1.00
118.87
ATOM
143
CB
MET
G
100
86.879
−139.768
112.510
1.00
119.67
ATOM
144
CG
MET
G
100
86.385
−141.023
113.205
1.00
120.23
ATOM
145
SD
MET
G
100
87.433
−142.456
112.875
1.00
121.05
ATOM
146
CE
MET
G
100
86.737
−143.078
111.340
1.00
122.33
ATOM
147
N
VAL
G
101
87.887
−137.395
114.482
1.00
118.47
ATOM
148
CA
VAL
G
101
88.514
−137.038
115.748
1.00
117.12
ATOM
149
C
VAL
G
101
87.713
−135.967
116.472
1.00
115.61
ATOM
150
O
VAL
G
101
87.466
−136.072
117.671
1.00
114.97
ATOM
151
CB
VAL
G
101
89.943
−136.515
115.529
1.00
117.83
ATOM
152
CG1
VAL
G
101
90.577
−136.163
116.863
1.00
119.14
ATOM
153
CG2
VAL
G
101
90.770
−137.564
114.807
1.00
118.81
ATOM
154
N
GLU
G
102
87.305
−134.938
115.738
1.00
115.04
ATOM
155
CA
GLU
G
102
86.523
−133.862
116.330
1.00
115.24
ATOM
156
C
GLU
G
102
85.146
−134.344
116.762
1.00
114.28
ATOM
157
O
GLU
G
102
84.557
−133.812
117.702
1.00
113.48
ATOM
158
CB
GLU
G
102
86.367
−132.695
115.347
1.00
116.69
ATOM
159
CG
GLU
G
102
87.576
−131.763
115.267
1.00
118.95
ATOM
160
CD
GLU
G
102
88.647
−132.239
114.301
1.00
120.98
ATOM
161
OE1
GLU
G
102
88.576
−131.886
113.102
1.00
121.42
ATOM
162
OE2
GLU
G
102
89.561
−132.969
114.738
1.00
121.86
ATOM
163
N
GLN
G
103
84.634
−135.357
116.076
1.00
114.05
ATOM
164
CA
GLN
G
103
83.319
−135.893
116.395
1.00
114.16
ATOM
165
C
GLN
G
103
83.404
−136.708
117.681
1.00
113.15
ATOM
166
O
GLN
G
103
82.510
−136.657
118.525
1.00
113.27
ATOM
167
CB
GLN
G
103
82.824
−136.756
115.230
1.00
116.01
ATOM
168
CG
GLN
G
103
81.313
−136.831
115.089
1.00
118.46
ATOM
169
CD
GLN
G
103
80.887
−137.109
113.660
1.00
120.20
ATOM
170
OE1
GLN
G
103
81.169
−138.173
113.109
1.00
121.62
ATOM
171
NE2
GLN
G
103
80.208
−136.143
113.048
1.00
120.70
ATOM
172
N
MET
G
104
84.497
−137.450
117.823
1.00
112.25
ATOM
173
CA
MET
G
104
84.730
−138.274
119.004
1.00
111.54
ATOM
174
C
MET
G
104
84.838
−137.376
120.232
1.00
112.25
ATOM
175
O
MET
G
104
84.313
−137.689
121.299
1.00
112.78
ATOM
176
CB
MET
G
104
86.028
−139.071
118.840
1.00
110.90
ATOM
177
CG
MET
G
104
86.435
−139.867
120.071
1.00
109.19
ATOM
178
SD
MET
G
104
85.518
−141.402
120.304
1.00
108.60
ATOM
179
CE
MET
G
104
86.816
−142.479
120.947
1.00
106.86
ATOM
180
N
GLN
G
105
85.530
−136.256
120.063
1.00
112.10
ATOM
181
CA
GLN
G
105
85.726
−135.286
121.134
1.00
111.89
ATOM
182
C
GLN
G
105
84.399
−134.844
121.744
1.00
112.91
ATOM
183
O
GLN
G
105
84.246
−134.807
122.963
1.00
113.09
ATOM
184
CB
GLN
G
105
86.475
−134.064
120.588
1.00
110.93
ATOM
185
CG
GLN
G
105
86.461
−132.848
121.498
1.00
108.92
ATOM
186
CD
GLN
G
105
87.579
−132.849
122.518
1.00
108.26
ATOM
187
OE1
GLN
G
105
87.613
−132.002
123.408
1.00
108.65
ATOM
188
NE2
GLN
G
105
88.505
−133.792
122.388
1.00
108.60
ATOM
189
N
GLU
G
106
83.443
−134.516
120.882
1.00
113.95
ATOM
190
CA
GLU
G
106
82.123
−134.062
121.310
1.00
114.14
ATOM
191
C
GLU
G
106
81.423
−135.064
122.216
1.00
112.47
ATOM
192
O
GLU
G
106
80.694
−134.683
123.129
1.00
111.33
ATOM
193
CB
GLU
G
106
81.240
−133.790
120.085
1.00
117.22
ATOM
194
CG
GLU
G
106
81.847
−132.829
119.069
1.00
121.88
ATOM
195
CD
GLU
G
106
81.831
−131.385
119.534
1.00
124.83
ATOM
196
OE1
GLU
G
106
80.725
−130.827
119.702
1.00
127.31
ATOM
197
OE2
GLU
G
106
82.922
−130.809
119.731
1.00
125.75
ATOM
198
N
ASP
G
107
81.651
−136.347
121.961
1.00
112.07
ATOM
199
CA
ASP
G
107
81.025
−137.407
122.739
1.00
112.28
ATOM
200
C
ASP
G
107
81.683
−137.674
124.079
1.00
110.45
ATOM
201
O
ASP
G
107
81.034
−138.143
125.012
1.00
110.76
ATOM
202
CB
ASP
G
107
80.989
−138.693
121.918
1.00
114.84
ATOM
203
CG
ASP
G
107
79.945
−138.646
120.814
1.00
117.49
ATOM
204
OD1
ASP
G
107
78.775
−138.970
121.099
1.00
120.99
ATOM
205
OD2
ASP
G
107
80.294
−138.268
119.674
1.00
117.70
ATOM
206
N
ILE
G
108
82.972
−137.386
124.181
1.00
108.33
ATOM
207
CA
ILE
G
108
83.680
−137.603
125.432
1.00
106.57
ATOM
208
C
ILE
G
108
83.295
−136.515
126.419
1.00
104.72
ATOM
209
O
ILE
G
108
83.130
−136.771
127.611
1.00
105.07
ATOM
210
CB
ILE
G
108
85.194
−137.592
125.199
1.00
107.34
ATOM
211
CG1
ILE
G
108
85.570
−138.780
124.303
1.00
106.62
ATOM
212
CG2
ILE
G
108
85.931
−137.666
126.532
1.00
107.53
ATOM
213
CD1
ILE
G
108
86.711
−138.511
123.364
1.00
106.38
ATOM
214
N
ILE
G
109
83.140
−135.301
125.909
1.00
102.38
ATOM
215
CA
ILE
G
109
82.755
−134.174
126.740
1.00
100.25
ATOM
216
C
ILE
G
109
81.357
−134.416
127.284
1.00
99.75
ATOM
217
O
ILE
G
109
81.073
−134.128
128.443
1.00
100.09
ATOM
218
CB
ILE
G
109
82.758
−132.871
125.925
1.00
99.79
ATOM
219
CG1
ILE
G
109
84.181
−132.570
125.447
1.00
98.40
ATOM
220
CG2
ILE
G
109
82.219
−131.728
126.764
1.00
99.76
ATOM
221
CD1
ILE
G
109
84.271
−131.441
124.449
1.00
97.98
ATOM
222
N
SER
G
110
80.493
−134.963
126.436
1.00
99.49
ATOM
223
CA
SER
G
110
79.120
−135.258
126.819
1.00
99.12
ATOM
224
C
SER
G
110
79.098
−136.336
127.897
1.00
99.07
ATOM
225
O
SER
G
110
78.261
−136.317
128.797
1.00
98.54
ATOM
226
CB
SER
G
110
78.329
−135.732
125.601
1.00
99.18
ATOM
227
OG
SER
G
110
76.996
−136.053
125.961
1.00
99.12
ATOM
228
N
LEU
G
111
80.029
−137.276
127.793
1.00
99.33
ATOM
229
CA
LEU
G
111
80.135
−138.364
128.755
1.00
100.48
ATOM
230
C
LEU
G
111
80.790
−137.873
130.041
1.00
101.49
ATOM
231
O
LEU
G
111
80.609
−138.458
131.109
1.00
101.29
ATOM
232
CB
LEU
G
111
80.952
−139.511
128.155
1.00
100.12
ATOM
233
CG
LEU
G
111
80.176
−140.676
127.531
1.00
100.14
ATOM
234
CD1
LEU
G
111
80.992
−141.321
126.426
1.00
100.57
ATOM
235
CD2
LEU
G
111
79.843
−141.684
128.621
1.00
100.82
ATOM
236
N
TRP
G
112
81.553
−136.791
129.928
1.00
103.03
ATOM
237
CA
TRP
G
112
82.238
−136.210
131.076
1.00
104.23
ATOM
238
C
TRP
G
112
81.265
−135.378
131.896
1.00
105.45
ATOM
239
O
TRP
G
112
81.329
−135.357
133.122
1.00
106.05
ATOM
240
CB
TRP
G
112
83.402
−135.326
130.612
1.00
103.46
ATOM
241
CG
TRP
G
112
84.730
−135.748
131.159
1.00
102.75
ATOM
242
CD1
TRP
G
112
85.403
−136.903
130.881
1.00
103.42
ATOM
243
CD2
TRP
G
112
85.550
−135.017
132.080
1.00
101.80
ATOM
244
NE1
TRP
G
112
86.593
−136.936
131.570
1.00
103.39
ATOM
245
CE2
TRP
G
112
86.708
−135.792
132.313
1.00
101.79
ATOM
246
CE3
TRP
G
112
85.418
−133.783
132.730
1.00
100.62
ATOM
247
CZ2
TRP
G
112
87.730
−135.371
133.171
1.00
100.65
ATOM
248
CZ3
TRP
G
112
86.435
−133.366
133.582
1.00
100.30
ATOM
249
CH2
TRP
G
112
87.576
−134.160
133.793
1.00
100.15
ATOM
250
N
ASP
G
113
80.361
−134.693
131.207
1.00
106.82
ATOM
251
CA
ASP
G
113
79.376
−133.862
131.879
1.00
108.44
ATOM
252
C
ASP
G
113
78.342
−134.672
132.643
1.00
108.41
ATOM
253
O
ASP
G
113
77.709
−134.157
133.563
1.00
108.64
ATOM
254
CB
ASP
G
113
78.673
−132.951
130.875
1.00
110.86
ATOM
255
CG
ASP
G
113
79.477
−131.700
130.566
1.00
113.42
ATOM
256
OD1
ASP
G
113
79.640
−130.866
131.479
1.00
116.27
ATOM
257
OD2
ASP
G
113
79.955
−131.560
129.420
1.00
115.26
ATOM
258
N
GLN
G
114
78.160
−135.936
132.273
1.00
107.17
ATOM
259
CA
GLN
G
114
77.188
−136.766
132.974
1.00
106.10
ATOM
260
C
GLN
G
114
77.874
−137.744
133.923
1.00
103.76
ATOM
261
O
GLN
G
114
77.242
−138.651
134.461
1.00
104.43
ATOM
262
CB
GLN
G
114
76.300
−137.527
131.980
1.00
109.06
ATOM
263
CG
GLN
G
114
77.005
−138.596
131.161
1.00
113.60
ATOM
264
CD
GLN
G
114
76.029
−139.502
130.422
1.00
116.46
ATOM
265
OE1
GLN
G
114
75.346
−139.076
129.488
1.00
118.64
ATOM
266
NE2
GLN
G
114
75.951
−140.758
130.850
1.00
116.28
ATOM
267
N
SER
G
115
79.172
−137.543
134.127
1.00
100.33
ATOM
268
CA
SER
G
115
79.956
−138.393
135.014
1.00
96.91
ATOM
269
C
SER
G
115
80.706
−137.560
136.051
1.00
93.15
ATOM
270
O
SER
G
115
80.543
−137.758
137.255
1.00
93.21
ATOM
271
CB
SER
G
115
80.946
−139.233
134.203
1.00
99.27
ATOM
272
OG
SER
G
115
80.275
−140.234
133.457
1.00
102.68
ATOM
273
N
LEU
G
116
81.527
−136.629
135.581
1.00
88.46
ATOM
274
CA
LEU
G
116
82.290
−135.766
136.475
1.00
84.39
ATOM
275
C
LEU
G
116
81.741
−134.347
136.459
1.00
82.46
ATOM
276
O
LEU
G
116
81.977
−133.591
135.519
1.00
82.86
ATOM
277
CB
LEU
G
116
83.767
−135.750
136.068
1.00
83.85
ATOM
278
CG
LEU
G
116
84.646
−136.857
136.656
1.00
82.12
ATOM
279
CD1
LEU
G
116
85.974
−136.902
135.922
1.00
82.50
ATOM
280
CD2
LEU
G
116
84.854
−136.596
138.144
1.00
80.96
ATOM
281
N
LYS
G
117
81.000
−133.995
137.503
1.00
80.71
ATOM
282
CA
LYS
G
117
80.407
−132.668
137.619
1.00
80.17
ATOM
283
C
LYS
G
117
81.100
−131.822
138.683
1.00
77.80
ATOM
284
O
LYS
G
117
81.342
−132.288
139.797
1.00
77.93
ATOM
285
CB
LYS
G
117
78.921
−132.780
137.955
1.00
82.16
ATOM
286
CG
LYS
G
117
77.997
−133.018
136.772
1.00
85.17
ATOM
287
CD
LYS
G
117
76.551
−132.954
137.242
1.00
87.66
ATOM
288
CE
LYS
G
117
75.607
−132.504
136.137
1.00
90.61
ATOM
289
NZ
LYS
G
117
74.283
−132.090
136.692
1.00
87.92
ATOM
290
N
PRO
G
118
81.420
−130.558
138.355
1.00
75.68
ATOM
291
CA
PRO
G
118
82.088
−129.645
139.284
1.00
74.22
ATOM
292
C
PRO
G
118
81.059
−129.021
140.206
1.00
73.71
ATOM
293
O
PRO
G
118
79.881
−128.947
139.863
1.00
75.64
ATOM
294
CB
PRO
G
118
82.709
−128.596
138.358
1.00
73.60
ATOM
295
CG
PRO
G
118
82.659
−129.228
136.975
1.00
74.73
ATOM
296
CD
PRO
G
118
81.352
−129.945
137.022
1.00
75.01
ATOM
297
N
CYS
G
119
81.481
−128.570
141.377
1.00
73.04
ATOM
298
CA
CYS
G
119
80.517
−127.953
142.264
1.00
73.80
ATOM
299
C
CYS
G
119
80.324
−126.491
141.888
1.00
72.46
ATOM
300
O
CYS
G
119
79.284
−125.907
142.171
1.00
73.82
ATOM
301
CB
CYS
G
119
80.944
−128.105
143.722
1.00
77.08
ATOM
302
SG
CYS
G
119
79.924
−129.360
144.564
1.00
86.22
ATOM
303
N
VAL
G
120
81.326
−125.907
141.241
1.00
69.39
ATOM
304
CA
VAL
G
120
81.247
−124.524
140.795
1.00
66.24
ATOM
305
C
VAL
G
120
81.939
−124.437
139.445
1.00
66.78
ATOM
306
O
VAL
G
120
83.008
−125.008
139.260
1.00
67.35
ATOM
307
CB
VAL
G
120
81.964
−123.562
141.757
1.00
65.45
ATOM
308
CG1
VAL
G
120
81.757
−122.128
141.292
1.00
64.25
ATOM
309
CG2
VAL
G
120
81.448
−123.745
143.167
1.00
65.16
ATOM
310
N
LYS
G
121
81.321
−123.744
138.498
1.00
68.69
ATOM
311
CA
LYS
G
121
81.903
−123.590
137.170
1.00
71.74
ATOM
312
C
LYS
G
121
82.060
−122.128
136.796
1.00
74.27
ATOM
313
O
LYS
G
121
81.131
−121.337
136.959
1.00
76.19
ATOM
314
CB
LYS
G
121
81.033
−124.260
136.099
1.00
72.94
ATOM
315
CG
LYS
G
121
81.448
−125.664
135.700
1.00
75.20
ATOM
316
CD
LYS
G
121
80.779
−126.073
134.387
1.00
77.11
ATOM
317
CE
LYS
G
121
81.061
−127.533
134.049
1.00
78.09
ATOM
318
NZ
LYS
G
121
80.615
−127.906
132.674
1.00
79.45
ATOM
319
N
LEU
G
122
83.233
−121.767
136.290
1.00
76.38
ATOM
320
CA
LEU
G
122
83.473
−120.394
135.863
1.00
79.17
ATOM
321
C
LEU
G
122
83.757
−120.376
134.371
1.00
81.74
ATOM
322
O
LEU
G
122
84.701
−121.010
133.905
1.00
82.55
ATOM
323
CB
LEU
G
122
84.657
−119.785
136.611
1.00
79.45
ATOM
324
CG
LEU
G
122
84.274
−118.875
137.779
1.00
78.85
ATOM
325
CD1
LEU
G
122
83.608
−119.695
138.873
1.00
77.90
ATOM
326
CD2
LEU
G
122
85.521
−118.189
138.306
1.00
79.94
ATOM
327
N
THR
G
123
82.938
−119.641
133.629
1.00
85.43
ATOM
328
CA
THR
G
123
83.092
−119.563
132.186
1.00
90.13
ATOM
329
C
THR
G
123
83.058
−118.134
131.670
1.00
93.59
ATOM
330
O
THR
G
123
82.259
−117.321
132.126
1.00
94.38
ATOM
331
CB
THR
G
123
81.968
−120.333
131.489
1.00
91.32
ATOM
332
OG1
THR
G
123
81.834
−121.630
132.076
1.00
93.24
ATOM
333
CG2
THR
G
123
82.256
−120.494
130.011
1.00
91.25
ATOM
334
N
PRO
G
124
83.927
−117.810
130.700
1.00
97.34
ATOM
335
CA
PRO
G
124
83.953
−116.456
130.148
1.00
100.80
ATOM
336
C
PRO
G
124
82.656
−116.141
129.415
1.00
103.51
ATOM
337
O
PRO
G
124
82.392
−116.686
128.346
1.00
104.31
ATOM
338
CB
PRO
G
124
85.163
−116.493
129.211
1.00
100.91
ATOM
339
CG
PRO
G
124
86.068
−117.489
129.882
1.00
100.12
ATOM
340
CD
PRO
G
124
85.075
−118.584
130.199
1.00
98.73
ATOM
341
N
LEU
G
125
81.838
−115.271
129.994
1.00
107.90
ATOM
342
CA
LEU
G
125
80.575
−114.898
129.366
1.00
112.76
ATOM
343
C
LEU
G
125
80.861
−113.904
128.250
1.00
116.09
ATOM
344
O
LEU
G
125
80.624
−112.709
128.406
1.00
116.30
ATOM
345
CB
LEU
G
125
79.648
−114.256
130.398
1.00
113.40
ATOM
346
CG
LEU
G
125
78.192
−114.016
129.992
1.00
113.32
ATOM
347
CD1
LEU
G
125
77.403
−115.309
130.161
1.00
114.30
ATOM
348
CD2
LEU
G
125
77.599
−112.929
130.874
1.00
114.10
ATOM
349
N
CYS
G
126
81.378
−114.395
127.128
1.00
119.58
ATOM
350
CA
CYS
G
126
81.708
−113.515
126.016
1.00
122.95
ATOM
351
C
CYS
G
126
80.573
−113.191
125.057
1.00
125.81
ATOM
352
O
CYS
G
126
80.494
−113.734
123.953
1.00
126.35
ATOM
353
CB
CYS
G
126
82.901
−114.067
125.236
1.00
122.36
ATOM
354
SG
CYS
G
126
84.494
−113.726
126.046
1.00
121.90
ATOM
355
N
VAL
G
127
79.696
−112.296
125.497
1.00
129.15
ATOM
356
CA
VAL
G
127
78.566
−111.852
124.693
1.00
131.76
ATOM
357
C
VAL
G
127
78.834
−110.393
124.326
1.00
132.26
ATOM
358
O
VAL
G
127
79.182
−109.582
125.187
1.00
132.30
ATOM
359
CB
VAL
G
127
77.241
−111.952
125.483
1.00
132.38
ATOM
360
CG1
VAL
G
127
77.304
−111.072
126.721
1.00
133.33
ATOM
361
CG2
VAL
G
127
76.075
−111.553
124.595
1.00
133.20
ATOM
362
N
GLY
G
128
78.684
−110.063
123.048
1.00
131.94
ATOM
363
CA
GLY
G
128
78.941
−108.702
122.614
1.00
131.82
ATOM
364
C
GLY
G
128
80.436
−108.454
122.541
1.00
131.76
ATOM
365
O
GLY
G
128
81.051
−108.049
123.527
1.00
131.75
ATOM
366
N
ALA
G
129
81.009
−108.709
121.367
1.00
131.69
ATOM
367
CA
ALA
G
129
82.439
−108.541
121.102
1.00
131.75
ATOM
368
C
ALA
G
129
83.240
−107.898
122.232
1.00
132.17
ATOM
369
O
ALA
G
129
84.144
−108.523
122.787
1.00
132.86
ATOM
370
CB
ALA
G
129
82.632
−107.748
119.819
1.00
131.22
ATOM
371
N
GLY
G
130
82.913
−106.649
122.558
1.00
131.78
ATOM
372
CA
GLY
G
130
83.615
−105.949
123.621
1.00
130.67
ATOM
373
C
GLY
G
130
84.005
−106.869
124.763
1.00
130.19
ATOM
374
O
GLY
G
130
83.255
−107.782
125.104
1.00
130.65
ATOM
375
N
SER
G
195
85.182
−106.632
125.341
1.00
128.61
ATOM
376
CA
SER
G
195
85.705
−107.429
126.454
1.00
126.30
ATOM
377
C
SER
G
195
84.590
−108.085
127.275
1.00
125.16
ATOM
378
O
SER
G
195
83.538
−107.483
127.495
1.00
125.28
ATOM
379
CB
SER
G
195
86.570
−106.538
127.345
1.00
125.36
ATOM
380
OG
SER
G
195
87.524
−105.831
126.567
1.00
121.97
ATOM
381
N
CYS
G
196
84.830
−109.311
127.740
1.00
122.96
ATOM
382
CA
CYS
G
196
83.821
−110.058
128.490
1.00
120.58
ATOM
383
C
CYS
G
196
83.992
−110.143
130.010
1.00
118.42
ATOM
384
O
CYS
G
196
84.973
−109.664
130.580
1.00
117.88
ATOM
385
CB
CYS
G
196
83.720
−111.480
127.931
1.00
120.97
ATOM
386
SG
CYS
G
196
84.469
−111.710
126.286
1.00
122.59
ATOM
387
N
ASP
G
197
83.008
−110.771
130.649
1.00
115.33
ATOM
388
CA
ASP
G
197
82.992
−110.960
132.095
1.00
112.91
ATOM
389
C
ASP
G
197
82.935
−112.461
132.366
1.00
111.21
ATOM
390
O
ASP
G
197
82.951
−113.257
131.431
1.00
111.48
ATOM
391
CB
ASP
G
197
81.766
−110.273
132.701
1.00
114.40
ATOM
392
CG
ASP
G
197
81.916
−110.021
134.191
1.00
116.21
ATOM
393
OD1
ASP
G
197
82.826
−109.253
134.563
1.00
118.31
ATOM
394
OD2
ASP
G
197
81.132
−110.590
134.980
1.00
116.81
ATOM
395
N
THR
G
198
82.848
−112.849
133.633
1.00
108.94
ATOM
396
CA
THR
G
198
82.796
−114.265
133.987
1.00
106.71
ATOM
397
C
THR
G
198
81.395
−114.729
134.392
1.00
104.11
ATOM
398
O
THR
G
198
80.627
−113.974
134.988
1.00
105.56
ATOM
399
CB
THR
G
198
83.760
−114.574
135.144
1.00
108.19
ATOM
400
OG1
THR
G
198
83.441
−113.738
136.263
1.00
109.13
ATOM
401
CG2
THR
G
198
85.190
−114.315
134.729
1.00
108.79
ATOM
402
N
SER
G
199
81.071
−115.978
134.068
1.00
101.10
ATOM
403
CA
SER
G
199
79.765
−116.555
134.395
1.00
98.61
ATOM
404
C
SER
G
199
79.905
−117.657
135.444
1.00
96.43
ATOM
405
O
SER
G
199
80.584
−118.661
135.216
1.00
96.37
ATOM
406
CB
SER
G
199
79.113
−117.124
133.130
1.00
98.18
ATOM
407
OG
SER
G
199
77.821
−117.635
133.406
1.00
96.50
ATOM
408
N
VAL
G
200
79.247
−117.479
136.584
1.00
92.80
ATOM
409
CA
VAL
G
200
79.331
−118.454
137.664
1.00
89.88
ATOM
410
C
VAL
G
200
78.074
−119.310
137.797
1.00
87.32
ATOM
411
O
VAL
G
200
76.954
−118.798
137.747
1.00
86.48
ATOM
412
CB
VAL
G
200
79.568
−117.749
139.012
1.00
90.70
ATOM
413
CG1
VAL
G
200
80.051
−118.755
140.045
1.00
90.81
ATOM
414
CG2
VAL
G
200
80.568
−116.621
138.831
1.00
91.35
ATOM
415
N
ILE
G
201
78.270
−120.614
137.976
1.00
84.68
ATOM
416
CA
ILE
G
201
77.164
−121.552
138.132
1.00
81.86
ATOM
417
C
ILE
G
201
77.483
−122.552
139.234
1.00
79.73
ATOM
418
O
ILE
G
201
78.516
−123.210
139.197
1.00
79.56
ATOM
419
CB
ILE
G
201
76.904
−122.366
136.840
1.00
82.08
ATOM
420
CG1
ILE
G
201
76.600
−121.432
135.666
1.00
85.27
ATOM
421
CG2
ILE
G
201
75.733
−123.311
137.055
1.00
78.87
ATOM
422
CD1
ILE
G
201
77.830
−120.796
135.047
1.00
89.69
ATOM
423
N
THR
G
202
76.600
−122.667
140.216
1.00
78.11
ATOM
424
CA
THR
G
202
76.812
−123.613
141.299
1.00
79.05
ATOM
425
C
THR
G
202
75.852
−124.794
141.137
1.00
80.92
ATOM
426
O
THR
G
202
74.653
−124.609
140.906
1.00
81.00
ATOM
427
CB
THR
G
202
76.575
−122.964
142.667
1.00
78.00
ATOM
428
OG1
THR
G
202
75.243
−122.452
142.725
1.00
79.43
ATOM
429
CG2
THR
G
202
77.549
−121.842
142.901
1.00
77.99
ATOM
430
N
GLN
G
203
76.384
−126.007
141.249
1.00
81.69
ATOM
431
CA
GLN
G
203
75.571
−127.207
141.104
1.00
81.90
ATOM
432
C
GLN
G
203
76.077
−128.353
141.977
1.00
83.87
ATOM
433
O
GLN
G
203
77.208
−128.325
142.457
1.00
84.27
ATOM
434
CB
GLN
G
203
75.548
−127.628
139.635
1.00
80.36
ATOM
435
CG
GLN
G
203
76.918
−127.643
138.979
1.00
79.24
ATOM
436
CD
GLN
G
203
76.859
−128.040
137.514
1.00
80.19
ATOM
437
OE1
GLN
G
203
76.167
−127.412
136.714
1.00
79.78
ATOM
438
NE2
GLN
G
203
77.589
−129.090
137.157
1.00
80.36
ATOM
439
N
ALA
G
204
75.232
−129.359
142.181
1.00
86.42
ATOM
440
CA
ALA
G
204
75.593
−130.514
143.003
1.00
87.19
ATOM
441
C
ALA
G
204
76.718
−131.315
142.355
1.00
87.49
ATOM
442
O
ALA
G
204
76.692
−131.563
141.156
1.00
85.76
ATOM
443
CB
ALA
G
204
74.366
−131.405
143.209
1.00
86.04
ATOM
444
N
CYS
G
205
77.702
−131.728
143.149
1.00
89.57
ATOM
445
CA
CYS
G
205
78.808
−132.510
142.609
1.00
93.38
ATOM
446
C
CYS
G
205
79.087
−133.832
143.328
1.00
96.85
ATOM
447
O
CYS
G
205
79.822
−133.876
144.314
1.00
96.56
ATOM
448
CB
CYS
G
205
80.083
−131.668
142.558
1.00
92.11
ATOM
449
SG
CYS
G
205
80.806
−131.144
144.146
1.00
93.23
ATOM
450
N
PRO
G
206
78.506
−134.938
142.826
1.00
100.89
ATOM
451
CA
PRO
G
206
78.691
−136.266
143.416
1.00
105.01
ATOM
452
C
PRO
G
206
80.095
−136.768
143.099
1.00
109.65
ATOM
453
O
PRO
G
206
80.606
−136.538
142.004
1.00
110.64
ATOM
454
CB
PRO
G
206
77.621
−137.107
142.719
1.00
103.87
ATOM
455
CG
PRO
G
206
76.607
−136.099
142.253
1.00
102.48
ATOM
456
CD
PRO
G
206
77.497
−135.000
141.757
1.00
102.04
ATOM
457
N
LYS
G
207
80.719
−137.456
144.044
1.00
114.22
ATOM
458
CA
LYS
G
207
82.064
−137.960
143.823
1.00
119.19
ATOM
459
C
LYS
G
207
82.101
−139.371
143.241
1.00
123.01
ATOM
460
O
LYS
G
207
82.701
−140.267
143.830
1.00
124.82
ATOM
461
CB
LYS
G
207
82.851
−137.922
145.139
1.00
119.60
ATOM
462
CG
LYS
G
207
83.462
−136.565
145.466
1.00
119.01
ATOM
463
CD
LYS
G
207
84.876
−136.473
144.916
1.00
118.82
ATOM
464
CE
LYS
G
207
85.454
−135.076
145.044
1.00
117.77
ATOM
465
NZ
LYS
G
207
84.868
−134.134
144.051
1.00
116.94
ATOM
466
N
ILE
G
208
81.466
−139.574
142.091
1.00
127.08
ATOM
467
CA
ILE
G
208
81.482
−140.893
141.466
1.00
131.24
ATOM
468
C
ILE
G
208
82.668
−141.008
140.512
1.00
132.68
ATOM
469
O
ILE
G
208
83.143
−140.004
139.984
1.00
133.21
ATOM
470
CB
ILE
G
208
80.184
−141.174
140.682
1.00
132.20
ATOM
471
CG1
ILE
G
208
79.995
−140.133
139.584
1.00
132.98
ATOM
472
CG2
ILE
G
208
78.995
−141.165
141.622
1.00
132.23
ATOM
473
CD1
ILE
G
208
78.847
−140.446
138.655
1.00
134.64
ATOM
474
N
SER
G
209
83.138
−142.234
140.295
1.00
134.15
ATOM
475
CA
SER
G
209
84.284
−142.480
139.429
1.00
135.70
ATOM
476
C
SER
G
209
83.970
−142.546
137.938
1.00
137.12
ATOM
477
O
SER
G
209
83.009
−143.192
137.517
1.00
138.29
ATOM
478
CB
SER
G
209
84.979
−143.779
139.850
1.00
134.98
ATOM
479
OG
SER
G
209
84.086
−144.875
139.771
1.00
135.08
ATOM
480
N
PHE
G
210
84.798
−141.869
137.146
1.00
137.24
ATOM
481
CA
PHE
G
210
84.660
−141.858
135.694
1.00
137.12
ATOM
482
C
PHE
G
210
85.467
−143.033
135.152
1.00
138.23
ATOM
483
O
PHE
G
210
86.687
−142.950
135.018
1.00
138.35
ATOM
484
CB
PHE
G
210
85.200
−140.546
135.121
1.00
136.15
ATOM
485
CG
PHE
G
210
85.309
−140.538
133.623
1.00
135.14
ATOM
486
CD1
PHE
G
210
84.170
−140.630
132.828
1.00
134.46
ATOM
487
CD2
PHE
G
210
86.550
−140.429
133.003
1.00
134.03
ATOM
488
CE1
PHE
G
210
84.266
−140.612
131.436
1.00
133.36
ATOM
489
CE2
PHE
G
210
86.657
−140.409
131.614
1.00
133.27
ATOM
490
CZ
PHE
G
210
85.513
−140.499
130.829
1.00
133.06
ATOM
491
N
GLU
G
211
84.774
−144.126
134.852
1.00
139.29
ATOM
492
CA
GLU
G
211
85.408
−145.342
134.347
1.00
140.31
ATOM
493
C
GLU
G
211
85.710
−145.289
132.849
1.00
140.01
ATOM
494
O
GLU
G
211
84.856
−144.906
132.049
1.00
139.77
ATOM
495
CB
GLU
G
211
84.515
−146.543
134.648
1.00
141.10
ATOM
496
CG
GLU
G
211
84.410
−146.875
136.128
1.00
143.21
ATOM
497
CD
GLU
G
211
83.070
−147.479
136.492
1.00
144.76
ATOM
498
OE1
GLU
G
211
82.970
−148.106
137.568
1.00
145.16
ATOM
499
OE2
GLU
G
211
82.114
−147.317
135.704
1.00
146.11
ATOM
500
N
PRO
G
212
86.933
−145.685
132.452
1.00
139.56
ATOM
501
CA
PRO
G
212
87.358
−145.686
131.050
1.00
139.07
ATOM
502
C
PRO
G
212
86.618
−146.766
130.271
1.00
138.18
ATOM
503
O
PRO
G
212
87.206
−147.771
129.876
1.00
138.23
ATOM
504
CB
PRO
G
212
88.858
−145.974
131.143
1.00
139.58
ATOM
505
CG
PRO
G
212
89.224
−145.516
132.532
1.00
139.85
ATOM
506
CD
PRO
G
212
88.063
−146.041
133.324
1.00
139.87
ATOM
507
N
ILE
G
213
85.327
−146.555
130.049
1.00
136.58
ATOM
508
CA
ILE
G
213
84.515
−147.525
129.329
1.00
134.44
ATOM
509
C
ILE
G
213
84.844
−147.553
127.836
1.00
133.16
ATOM
510
O
ILE
G
213
84.751
−146.535
127.154
1.00
133.40
ATOM
511
CB
ILE
G
213
83.025
−147.221
129.538
1.00
134.18
ATOM
512
CG1
ILE
G
213
82.170
−148.233
128.780
1.00
133.60
ATOM
513
CG2
ILE
G
213
82.728
−145.797
129.093
1.00
134.56
ATOM
514
CD1
ILE
G
213
80.713
−148.192
129.175
1.00
134.43
ATOM
515
N
PRO
G
214
85.234
−148.730
127.316
1.00
131.77
ATOM
516
CA
PRO
G
214
85.590
−148.929
125.907
1.00
130.01
ATOM
517
C
PRO
G
214
84.603
−148.292
124.933
1.00
128.02
ATOM
518
O
PRO
G
214
83.390
−148.418
125.097
1.00
126.87
ATOM
519
CB
PRO
G
214
85.637
−150.449
125.787
1.00
130.90
ATOM
520
CG
PRO
G
214
86.169
−150.848
127.130
1.00
131.42
ATOM
521
CD
PRO
G
214
85.294
−150.012
128.043
1.00
131.68
ATOM
522
N
ILE
G
215
85.131
−147.609
123.922
1.00
126.22
ATOM
523
CA
ILE
G
215
84.297
−146.949
122.928
1.00
124.39
ATOM
524
C
ILE
G
215
84.606
−147.439
121.517
1.00
123.82
ATOM
525
O
ILE
G
215
85.758
−147.432
121.089
1.00
123.83
ATOM
526
CB
ILE
G
215
84.498
−145.419
122.972
1.00
124.52
ATOM
527
CG1
ILE
G
215
83.798
−144.853
124.204
1.00
124.66
ATOM
528
CG2
ILE
G
215
83.946
−144.775
121.712
1.00
123.95
ATOM
529
CD1
ILE
G
215
82.301
−145.085
124.207
1.00
126.40
ATOM
530
N
HIS
G
216
83.567
−147.855
120.801
1.00
122.91
ATOM
531
CA
HIS
G
216
83.707
−148.337
119.436
1.00
122.26
ATOM
532
C
HIS
G
216
83.005
−147.378
118.487
1.00
122.82
ATOM
533
O
HIS
G
216
81.782
−147.263
118.512
1.00
122.59
ATOM
534
CB
HIS
G
216
83.064
−149.719
119.279
1.00
121.11
ATOM
535
CG
HIS
G
216
83.602
−150.756
120.212
1.00
120.49
ATOM
536
ND1
HIS
G
216
84.919
−151.164
120.198
1.00
120.39
ATOM
537
CD2
HIS
G
216
82.988
−151.501
121.161
1.00
120.37
ATOM
538
CE1
HIS
G
216
85.091
−152.118
121.096
1.00
120.82
ATOM
539
NE2
HIS
G
216
83.935
−152.341
121.694
1.00
120.97
ATOM
540
N
TYR
G
217
83.767
−146.678
117.657
1.00
124.13
ATOM
541
CA
TYR
G
217
83.154
−145.780
116.686
1.00
126.48
ATOM
542
C
TYR
G
217
82.753
−146.675
115.523
1.00
129.20
ATOM
543
O
TYR
G
217
83.591
−147.022
114.699
1.00
129.59
ATOM
544
CB
TYR
G
217
84.159
−144.736
116.202
1.00
124.57
ATOM
545
CG
TYR
G
217
83.551
−143.677
115.308
1.00
123.48
ATOM
546
CD1
TYR
G
217
82.990
−142.522
115.849
1.00
123.73
ATOM
547
CD2
TYR
G
217
83.531
−143.831
113.921
1.00
123.00
ATOM
548
CE1
TYR
G
217
82.427
−141.541
115.033
1.00
123.68
ATOM
549
CE2
TYR
G
217
82.969
−142.858
113.096
1.00
123.64
ATOM
550
CZ
TYR
G
217
82.420
−141.715
113.658
1.00
123.44
ATOM
551
OH
TYR
G
217
81.865
−140.755
112.843
1.00
122.11
ATOM
552
N
CYS
G
218
81.486
−147.070
115.462
1.00
132.82
ATOM
553
CA
CYS
G
218
81.054
−147.947
114.380
1.00
136.36
ATOM
554
C
CYS
G
218
80.480
−147.158
113.202
1.00
137.85
ATOM
555
O
CYS
G
218
80.050
−146.011
113.357
1.00
138.46
ATOM
556
CB
CYS
G
218
79.996
−148.934
114.866
1.00
137.77
ATOM
557
SG
CYS
G
218
80.410
−149.952
116.317
1.00
141.47
ATOM
558
N
ALA
G
219
80.464
−147.790
112.031
1.00
138.84
ATOM
559
CA
ALA
G
219
79.953
−147.180
110.806
1.00
139.87
ATOM
560
C
ALA
G
219
78.437
−147.322
110.652
1.00
140.76
ATOM
561
O
ALA
G
219
77.887
−148.416
110.788
1.00
140.94
ATOM
562
CB
ALA
G
219
80.656
−147.793
109.599
1.00
139.80
ATOM
563
N
PRO
G
220
77.747
−146.211
110.347
1.00
141.32
ATOM
564
CA
PRO
G
220
76.292
−146.186
110.168
1.00
142.02
ATOM
565
C
PRO
G
220
75.880
−146.886
108.878
1.00
142.66
ATOM
566
O
PRO
G
220
76.725
−147.227
108.052
1.00
143.05
ATOM
567
CB
PRO
G
220
75.973
−144.688
110.128
1.00
141.53
ATOM
568
CG
PRO
G
220
77.147
−144.054
110.841
1.00
141.13
ATOM
569
CD
PRO
G
220
78.287
−144.845
110.277
1.00
140.75
ATOM
570
N
ALA
G
221
74.580
−147.099
108.708
1.00
143.48
ATOM
571
CA
ALA
G
221
74.079
−147.743
107.503
1.00
143.71
ATOM
572
C
ALA
G
221
74.302
−146.806
106.325
1.00
142.82
ATOM
573
O
ALA
G
221
73.748
−145.708
106.284
1.00
142.96
ATOM
574
CB
ALA
G
221
72.603
−148.056
107.654
1.00
144.82
ATOM
575
N
GLY
G
222
75.115
−147.243
105.370
1.00
140.94
ATOM
576
CA
GLY
G
222
75.396
−146.417
104.209
1.00
138.32
ATOM
577
C
GLY
G
222
76.792
−145.835
104.279
1.00
136.29
ATOM
578
O
GLY
G
222
77.201
−145.050
103.424
1.00
136.34
ATOM
579
N
PHE
G
223
77.526
−146.238
105.311
1.00
134.39
ATOM
580
CA
PHE
G
223
78.890
−145.777
105.537
1.00
132.34
ATOM
581
C
PHE
G
223
79.777
−146.927
106.001
1.00
130.44
ATOM
582
O
PHE
G
223
79.291
−147.921
106.542
1.00
130.04
ATOM
583
CB
PHE
G
223
78.894
−144.670
106.592
1.00
132.84
ATOM
584
CG
PHE
G
223
78.252
−143.397
106.134
1.00
133.73
ATOM
585
CD1
PHE
G
223
78.935
−142.528
105.292
1.00
133.66
ATOM
586
CD2
PHE
G
223
76.967
−143.061
106.547
1.00
134.47
ATOM
587
CE1
PHE
G
223
78.352
−141.337
104.868
1.00
134.19
ATOM
588
CE2
PHE
G
223
76.371
−141.871
106.128
1.00
135.20
ATOM
589
CZ
PHE
G
223
77.067
−141.007
105.287
1.00
135.04
ATOM
590
N
ALA
G
224
81.081
−146.784
105.788
1.00
128.35
ATOM
591
CA
ALA
G
224
82.038
−147.806
106.189
1.00
126.17
ATOM
592
C
ALA
G
224
83.350
−147.160
106.618
1.00
124.72
ATOM
593
O
ALA
G
224
83.741
−146.125
106.083
1.00
124.65
ATOM
594
CB
ALA
G
224
82.280
−148.763
105.033
1.00
126.68
ATOM
595
N
ILE
G
225
84.028
−147.771
107.583
1.00
122.82
ATOM
596
CA
ILE
G
225
85.296
−147.238
108.062
1.00
121.00
ATOM
597
C
ILE
G
225
86.481
−148.096
107.630
1.00
119.79
ATOM
598
O
ILE
G
225
86.477
−149.316
107.801
1.00
119.03
ATOM
599
CB
ILE
G
225
85.293
−147.094
109.603
1.00
121.03
ATOM
600
CG1
ILE
G
225
84.767
−148.369
110.258
1.00
120.98
ATOM
601
CG2
ILE
G
225
84.438
−145.910
110.010
1.00
120.24
ATOM
602
CD1
ILE
G
225
85.843
−149.311
110.722
1.00
120.08
ATOM
603
N
LEU
G
226
87.488
−147.442
107.061
1.00
118.45
ATOM
604
CA
LEU
G
226
88.692
−148.108
106.575
1.00
117.87
ATOM
605
C
LEU
G
226
89.778
−148.170
107.644
1.00
117.93
ATOM
606
O
LEU
G
226
90.048
−147.181
108.320
1.00
117.78
ATOM
607
CB
LEU
G
226
89.233
−147.360
105.355
1.00
117.84
ATOM
608
CG
LEU
G
226
88.416
−147.465
104.067
1.00
117.99
ATOM
609
CD1
LEU
G
226
88.412
−146.134
103.329
1.00
117.75
ATOM
610
CD2
LEU
G
226
89.000
−148.571
103.202
1.00
118.64
ATOM
611
N
LYS
G
227
90.405
−149.333
107.784
1.00
118.28
ATOM
612
CA
LYS
G
227
91.465
−149.518
108.766
1.00
119.16
ATOM
613
C
LYS
G
227
92.802
−149.761
108.070
1.00
120.69
ATOM
614
O
LYS
G
227
93.016
−150.822
107.486
1.00
121.36
ATOM
615
CB
LYS
G
227
91.137
−150.710
109.674
1.00
117.69
ATOM
616
CG
LYS
G
227
92.124
−150.907
110.812
1.00
116.17
ATOM
617
CD
LYS
G
227
92.021
−152.297
111.418
1.00
115.50
ATOM
618
CE
LYS
G
227
93.166
−152.535
112.389
1.00
114.84
ATOM
619
NZ
LYS
G
227
93.253
−153.948
112.850
1.00
113.75
ATOM
620
N
CYS
G
228
93.701
−148.782
108.125
1.00
122.52
ATOM
621
CA
CYS
G
228
95.013
−148.931
107.494
1.00
124.88
ATOM
622
C
CYS
G
228
95.858
−149.909
108.317
1.00
125.15
ATOM
623
O
CYS
G
228
96.285
−149.591
109.427
1.00
125.31
ATOM
624
CB
CYS
G
228
95.704
−147.560
107.380
1.00
127.78
ATOM
625
SG
CYS
G
228
97.401
−147.576
106.702
1.00
132.08
ATOM
626
N
ASN
G
229
96.082
−151.103
107.768
1.00
125.50
ATOM
627
CA
ASN
G
229
96.859
−152.135
108.452
1.00
126.07
ATOM
628
C
ASN
G
229
98.350
−152.104
108.155
1.00
126.43
ATOM
629
O
ASN
G
229
99.019
−153.135
108.224
1.00
126.40
ATOM
630
CB
ASN
G
229
96.331
−153.533
108.114
1.00
127.05
ATOM
631
CG
ASN
G
229
95.052
−153.874
108.855
1.00
128.07
ATOM
632
OD1
ASN
G
229
93.960
−153.472
108.455
1.00
129.09
ATOM
633
ND2
ASN
G
229
95.185
−154.612
109.953
1.00
128.62
ATOM
634
N
ASP
G
230
98.873
−150.931
107.822
1.00
127.09
ATOM
635
CA
ASP
G
230
100.298
−150.803
107.541
1.00
128.18
ATOM
636
C
ASP
G
230
101.112
−151.040
108.808
1.00
129.06
ATOM
637
O
ASP
G
230
100.792
−150.501
109.867
1.00
129.47
ATOM
638
CB
ASP
G
230
100.611
−149.413
106.994
1.00
128.04
ATOM
639
CG
ASP
G
230
100.772
−149.400
105.486
1.00
128.21
ATOM
640
OD1
ASP
G
230
99.829
−149.813
104.784
1.00
129.16
ATOM
641
OD2
ASP
G
230
101.844
−148.972
105.012
1.00
127.80
ATOM
642
N
LYS
G
231
102.174
−151.832
108.693
1.00
130.19
ATOM
643
CA
LYS
G
231
103.034
−152.142
109.833
1.00
131.50
ATOM
644
C
LYS
G
231
103.705
−150.890
110.406
1.00
132.11
ATOM
645
O
LYS
G
231
103.862
−150.762
111.620
1.00
132.26
ATOM
646
CB
LYS
G
231
104.103
−153.164
109.420
1.00
131.22
ATOM
647
CG
LYS
G
231
103.545
−154.525
108.994
1.00
131.29
ATOM
648
CD
LYS
G
231
102.981
−155.296
110.185
1.00
131.06
ATOM
649
CE
LYS
G
231
102.249
−156.559
109.747
1.00
130.17
ATOM
650
NZ
LYS
G
231
101.640
−157.279
110.904
1.00
128.78
ATOM
651
N
THR
G
232
104.100
−149.970
109.531
1.00
132.72
ATOM
652
CA
THR
G
232
104.750
−148.738
109.960
1.00
133.16
ATOM
653
C
THR
G
232
104.170
−147.577
109.173
1.00
133.64
ATOM
654
O
THR
G
232
104.627
−147.283
108.072
1.00
134.29
ATOM
655
CB
THR
G
232
106.264
−148.791
109.698
1.00
133.30
ATOM
656
OG1
THR
G
232
106.807
−149.976
110.286
1.00
133.19
ATOM
657
CG2
THR
G
232
106.956
−147.583
110.304
1.00
134.01
ATOM
658
N
PHE
G
233
103.162
−146.923
109.741
1.00
133.70
ATOM
659
CA
PHE
G
233
102.506
−145.798
109.086
1.00
134.07
ATOM
660
C
PHE
G
233
102.979
−144.482
109.689
1.00
133.22
ATOM
661
O
PHE
G
233
103.185
−144.394
110.897
1.00
133.97
ATOM
662
CB
PHE
G
233
100.990
−145.927
109.240
1.00
135.95
ATOM
663
CG
PHE
G
233
100.211
−145.067
108.293
1.00
138.56
ATOM
664
CD1
PHE
G
233
100.413
−145.170
106.922
1.00
139.24
ATOM
665
CD2
PHE
G
233
99.267
−144.163
108.766
1.00
139.44
ATOM
666
CE1
PHE
G
233
99.687
−144.386
106.031
1.00
140.27
ATOM
667
CE2
PHE
G
233
98.534
−143.372
107.885
1.00
140.80
ATOM
668
CZ
PHE
G
233
98.744
−143.485
106.513
1.00
140.90
ATOM
669
N
ASN
G
234
103.137
−143.455
108.857
1.00
132.11
ATOM
670
CA
ASN
G
234
103.606
−142.163
109.353
1.00
131.12
ATOM
671
C
ASN
G
234
102.497
−141.209
109.789
1.00
130.16
ATOM
672
O
ASN
G
234
102.776
−140.083
110.195
1.00
130.18
ATOM
673
CB
ASN
G
234
104.479
−141.463
108.305
1.00
131.40
ATOM
674
CG
ASN
G
234
103.667
−140.844
107.184
1.00
131.18
ATOM
675
OD1
ASN
G
234
103.832
−139.666
106.859
1.00
130.27
ATOM
676
ND2
ASN
G
234
102.791
−141.636
106.581
1.00
130.32
ATOM
677
N
GLY
G
235
101.246
−141.649
109.711
1.00
128.79
ATOM
678
CA
GLY
G
235
100.152
−140.784
110.119
1.00
127.79
ATOM
679
C
GLY
G
235
99.372
−140.177
108.967
1.00
127.12
ATOM
680
O
GLY
G
235
98.186
−140.456
108.808
1.00
126.69
ATOM
681
N
LYS
G
236
100.023
−139.334
108.171
1.00
126.63
ATOM
682
CA
LYS
G
236
99.361
−138.704
107.031
1.00
126.89
ATOM
683
C
LYS
G
236
100.036
−139.113
105.726
1.00
128.87
ATOM
684
O
LYS
G
236
101.238
−239.357
105.693
1.00
129.74
ATOM
685
CB
LYS
G
236
99.386
−137.177
107.169
1.00
124.81
ATOM
686
CG
LYS
G
236
100.774
−136.597
107.412
1.00
122.07
ATOM
687
CD
LYS
G
236
100.770
−135.068
107.512
1.00
120.19
ATOM
688
CE
LYS
G
236
100.766
−134.390
106.146
1.00
118.90
ATOM
689
NZ
LYS
G
236
100.848
−132.901
106.254
1.00
116.47
ATOM
690
N
GLY
G
237
99.254
−139.183
104.654
1.00
130.44
ATOM
691
CA
GLY
G
237
99.797
−139.569
103.364
1.00
132.18
ATOM
692
C
GLY
G
237
99.066
−140.755
102.767
1.00
133.46
ATOM
693
O
GLY
G
237
97.921
−141.018
103.138
1.00
134.02
ATOM
694
N
PRO
G
238
99.693
−141.487
101.838
1.00
133.68
ATOM
695
CA
PRO
G
238
99.075
−142.651
101.200
1.00
133.81
ATOM
696
C
PRO
G
238
99.297
−143.951
101.985
1.00
133.94
ATOM
697
O
PRO
G
238
100.427
−144.267
102.353
1.00
133.93
ATOM
698
CB
PRO
G
238
99.759
−142.702
99.827
1.00
133.77
ATOM
699
CG
PRO
G
238
100.463
−141.336
99.685
1.00
134.36
ATOM
700
CD
PRO
G
238
100.886
−141.069
101.093
1.00
134.13
ATOM
701
N
CYS
G
239
98.228
−144.703
102.245
1.00
134.81
ATOM
702
CA
CYS
G
239
98.361
−145.976
102.959
1.00
136.32
ATOM
703
C
CYS
G
239
98.399
−147.104
101.926
1.00
136.72
ATOM
704
O
CYS
G
239
97.640
−147.086
100.958
1.00
136.38
ATOM
705
CB
CYS
G
239
97.187
−146.196
103.935
1.00
136.44
ATOM
706
SG
CYS
G
239
97.192
−147.860
104.696
1.00
136.59
ATOM
707
N
LYS
G
240
99.274
−148.086
102.136
1.00
138.05
ATOM
708
CA
LYS
G
240
99.405
−149.212
101.207
1.00
139.87
ATOM
709
C
LYS
G
240
98.342
−150.286
101.428
1.00
139.47
ATOM
710
O
LYS
G
240
97.436
−150.447
100.613
1.00
139.04
ATOM
711
CB
LYS
G
240
100.802
−149.837
101.324
1.00
141.13
ATOM
712
CG
LYS
G
240
101.941
−148.901
100.918
1.00
142.81
ATOM
713
CD
LYS
G
240
103.310
−149.526
101.173
1.00
143.74
ATOM
714
CE
LYS
G
240
104.429
−148.549
100.835
1.00
143.78
ATOM
715
NZ
LYS
G
240
105.786
−149.103
101.110
1.00
143.33
ATOM
716
N
ASN
G
241
98.458
−151.020
102.530
1.00
139.54
ATOM
717
CA
ASN
G
241
97.499
−152.070
102.850
1.00
139.69
ATOM
718
C
ASN
G
241
96.445
−151.535
103.811
1.00
139.92
ATOM
719
O
ASN
G
241
96.774
−151.092
104.908
1.00
139.69
ATOM
720
CB
ASN
G
241
98.207
−153.257
103.505
1.00
139.80
ATOM
721
CG
ASN
G
241
97.305
−154.468
103.640
1.00
140.13
ATOM
722
OD1
ASN
G
241
97.503
−155.314
104.512
1.00
139.63
ATOM
723
ND2
ASN
G
241
96.312
−154.563
102.763
1.00
139.93
ATOM
724
N
VAL
G
242
95.182
−151.588
103.405
1.00
139.96
ATOM
725
CA
VAL
G
242
94.098
−151.102
104.249
1.00
140.28
ATOM
726
C
VAL
G
242
92.840
−151.950
104.097
1.00
140.63
ATOM
727
O
VAL
G
242
92.326
−152.114
102.991
1.00
141.19
ATOM
728
CB
VAL
G
242
93.759
−149.631
103.905
1.00
140.31
ATOM
729
CG1
VAL
G
242
93.609
−149.479
102.400
1.00
139.72
ATOM
730
CG2
VAL
G
242
92.476
−149.210
104.607
1.00
140.48
ATOM
731
N
SER
G
243
92.350
−152.486
105.211
1.00
140.58
ATOM
732
CA
SER
G
243
91.149
−153.322
105.211
1.00
140.55
ATOM
733
C
SER
G
243
89.925
−152.489
105.588
1.00
140.69
ATOM
734
O
SER
G
243
90.002
−151.264
105.656
1.00
140.64
ATOM
735
CB
SER
G
243
91.308
−154.467
106.213
1.00
140.83
ATOM
736
OG
SER
G
243
91.381
−153.972
107.536
1.00
140.52
ATOM
737
N
THR
G
244
88.804
−153.157
105.845
1.00
141.03
ATOM
738
CA
THR
G
244
87.582
−152.460
106.212
1.00
141.52
ATOM
739
C
THR
G
244
86.765
−153.217
107.244
1.00
142.08
ATOM
740
O
THR
G
244
86.149
−154.231
106.927
1.00
141.97
ATOM
741
CB
THR
G
244
86.683
−152.231
104.983
1.00
141.57
ATOM
742
OG1
THR
G
244
87.375
−151.421
104.032
1.00
142.02
ATOM
743
CG2
THR
G
244
85.395
−151.532
105.384
1.00
140.17
ATOM
744
N
VAL
G
245
86.769
−152.726
108.476
1.00
142.71
ATOM
745
CA
VAL
G
245
86.005
−153.338
109.549
1.00
143.44
ATOM
746
C
VAL
G
245
84.747
−152.503
109.763
1.00
143.75
ATOM
747
O
VAL
G
245
84.627
−151.413
109.204
1.00
143.15
ATOM
748
CB
VAL
G
245
86.821
−153.377
110.853
1.00
144.12
ATOM
749
CG1
VAL
G
245
87.881
−154.460
110.778
1.00
144.77
ATOM
750
CG2
VAL
G
245
87.479
−152.032
111.086
1.00
144.53
ATOM
751
N
GLN
G
246
83.808
−153.006
110.557
1.00
144.36
ATOM
752
CA
GLN
G
246
82.577
−152.266
110.799
1.00
144.77
ATOM
753
C
GLN
G
246
82.652
−151.364
112.024
1.00
144.15
ATOM
754
O
GLN
G
246
82.087
−150.272
112.025
1.00
143.24
ATOM
755
CB
GLN
G
246
81.392
−153.227
110.918
1.00
146.20
ATOM
756
CG
GLN
G
246
81.220
−154.117
109.699
1.00
148.95
ATOM
757
CD
GLN
G
246
81.195
−153.327
108.400
1.00
150.00
ATOM
758
OE1
GLN
G
246
80.344
−152.461
108.202
1.00
150.67
ATOM
759
NE2
GLN
G
246
82.136
−153.623
107.510
1.00
149.89
ATOM
760
N
CYS
G
247
83.338
−151.814
113.069
1.00
143.81
ATOM
761
CA
CYS
G
247
83.474
−150.999
114.274
1.00
143.17
ATOM
762
C
CYS
G
247
84.949
−150.785
114.595
1.00
142.65
ATOM
763
O
CYS
G
247
85.796
−151.613
114.255
1.00
142.71
ATOM
764
CB
CYS
G
247
82.810
−151.662
115.485
1.00
142.99
ATOM
765
SG
CYS
G
247
80.988
−151.740
115.542
1.00
143.43
ATOM
766
N
THR
G
248
85.247
−149.676
115.262
1.00
141.73
ATOM
767
CA
THR
G
248
86.613
−149.336
115.640
1.00
140.76
ATOM
768
C
THR
G
248
87.070
−150.095
116.883
1.00
140.31
ATOM
769
O
THR
G
248
86.258
−150.456
117.731
1.00
140.20
ATOM
770
CB
THR
G
248
86.725
−147.838
115.923
1.00
140.39
ATOM
771
OG1
THR
G
248
86.168
−147.112
114.824
1.00
141.14
ATOM
772
CG2
THR
G
248
88.169
−147.433
116.094
1.00
140.10
ATOM
773
N
HIS
G
249
88.375
−150.325
116.991
1.00
139.86
ATOM
774
CA
HIS
G
249
88.932
−151.035
118.138
1.00
139.38
ATOM
775
C
HIS
G
249
88.597
−150.355
119.464
1.00
137.88
ATOM
776
O
HIS
G
249
88.282
−149.167
119.501
1.00
138.46
ATOM
777
CB
HIS
G
249
90.449
−151.170
117.990
1.00
140.83
ATOM
778
CG
HIS
G
249
90.872
−152.257
117.049
1.00
143.17
ATOM
779
ND1
HIS
G
249
90.448
−152.316
115.739
1.00
143.35
ATOM
780
CD2
HIS
G
249
91.689
−153.323
117.227
1.00
143.40
ATOM
781
CE1
HIS
G
249
90.986
−153.371
115.151
1.00
143.13
ATOM
782
NE2
HIS
G
249
91.743
−153.998
116.032
1.00
143.09
ATOM
783
N
GLY
G
250
88.672
−151.119
120.550
1.00
135.79
ATOM
784
CA
GLY
G
250
88.359
−150.585
121.865
1.00
132.31
ATOM
785
C
GLY
G
250
89.255
−149.450
122.328
1.00
129.65
ATOM
786
O
GLY
G
250
90.404
−149.674
122.714
1.00
129.34
ATOM
787
N
ILE
G
251
88.723
−148.232
122.302
1.00
126.82
ATOM
788
CA
ILE
G
251
89.464
−147.053
122.729
1.00
123.65
ATOM
789
C
ILE
G
251
89.083
−146.696
124.159
1.00
121.43
ATOM
790
O
ILE
G
251
87.906
−146.528
124.468
1.00
121.14
ATOM
791
CB
ILE
G
251
89.145
−145.841
121.836
1.00
123.65
ATOM
792
CG1
ILE
G
251
89.420
−146.199
120.375
1.00
124.47
ATOM
793
CG2
ILE
G
252
89.983
−144.643
122.259
1.00
122.65
ATOM
794
CD1
ILE
G
251
90.843
−146.656
120.116
1.00
125.76
ATOM
795
N
ARG
G
252
90.082
−146.581
125.025
1.00
119.23
ATOM
796
CA
ARG
G
252
89.857
−146.237
126.422
1.00
117.32
ATOM
797
C
ARG
G
252
89.886
−144.713
126.553
1.00
114.89
ATOM
798
O
ARG
G
252
90.918
−144.088
126.322
1.00
114.47
ATOM
799
CB
ARG
G
252
90.959
−146.854
127.291
1.00
119.04
ATOM
800
CG
ARG
G
252
91.398
−148.252
126.860
1.00
120.89
ATOM
801
CD
ARG
G
252
90.441
−149.350
127.320
1.00
123.64
ATOM
802
NE
ARG
G
252
90.658
−149.735
128.715
1.00
125.39
ATOM
803
CZ
ARG
G
252
90.032
−150.741
129.319
1.00
125.75
ATOM
804
NH1
ARG
G
252
89.145
−151.468
128.653
1.00
126.03
ATOM
805
NH2
ARG
G
252
90.296
−151.025
130.589
1.00
124.96
ATOM
806
N
PRO
G
253
88.749
−144.093
126.923
1.00
113.15
ATOM
807
CA
PRO
G
253
88.674
−142.635
127.073
1.00
112.07
ATOM
808
C
PRO
G
253
89.467
−142.080
128.254
1.00
111.17
ATOM
809
O
PRO
G
253
88.925
−141.891
129.346
1.00
111.86
ATOM
810
CB
PRO
G
253
87.178
−142.389
127.228
1.00
111.80
ATOM
811
CG
PRO
G
253
86.754
−143.589
128.011
1.00
112.54
ATOM
812
CD
PRO
G
253
87.441
−144.700
127.232
1.00
113.08
ATOM
813
N
VAL
G
254
90.746
−141.807
128.022
1.00
109.24
ATOM
814
CA
VAL
G
254
91.622
−141.274
129.057
1.00
106.74
ATOM
815
C
VAL
G
254
92.049
−139.851
128.722
1.00
106.15
ATOM
816
O
VAL
G
254
92.714
−139.615
127.712
1.00
105.35
ATOM
817
CB
VAL
G
254
92.894
−142.136
129.198
1.00
106.43
ATOM
818
CG1
VAL
G
254
93.815
−141.539
130.252
1.00
105.45
ATOM
819
CG2
VAL
G
254
92.516
−143.559
129.568
1.00
105.32
ATOM
820
N
VAL
G
255
91.659
−138.906
129.567
1.00
105.48
ATOM
821
CA
VAL
G
255
92.020
−137.511
129.363
1.00
104.38
ATOM
822
C
VAL
G
255
93.205
−137.137
130.244
1.00
102.82
ATOM
823
O
VAL
G
255
93.042
−136.827
131.423
1.00
103.17
ATOM
824
CB
VAL
G
255
90.835
−136.573
129.684
1.00
103.63
ATOM
825
CG1
VAL
G
255
89.960
−136.398
128.452
1.00
102.60
ATOM
826
CG2
VAL
G
255
90.013
−137.153
130.821
1.00
103.74
ATOM
827
N
SER
G
256
94.399
−137.177
129.664
1.00
101.35
ATOM
828
CA
SER
G
256
95.619
−136.849
130.391
1.00
100.45
ATOM
829
C
SER
G
256
96.587
−136.050
129.530
1.00
99.76
ATOM
830
O
SER
G
256
96.492
−136.053
128.304
1.00
99.01
ATOM
831
CB
SER
G
256
96.298
−138.133
130.875
1.00
100.56
ATOM
832
OG
SER
G
256
96.534
−139.020
129.799
1.00
100.95
ATOM
833
N
THR
G
257
97.529
−135.379
130.182
1.00
99.86
ATOM
834
CA
THR
G
257
98.513
−134.566
129.479
1.00
100.65
ATOM
835
C
THR
G
257
99.914
−135.174
129.524
1.00
101.63
ATOM
836
O
THR
G
257
100.217
−136.011
130.380
1.00
101.64
ATOM
837
CB
THR
G
257
98.581
−133.145
130.078
1.00
99.95
ATOM
838
OG1
THR
G
257
98.775
−133.230
131.496
1.00
97.28
ATOM
839
CG2
THR
G
257
97.307
−132.392
129.795
1.00
100.77
ATOM
840
N
GLN
G
258
100.762
−134.744
128.591
1.00
101.38
ATOM
841
CA
GLN
G
258
102.140
−135.218
128.506
1.00
101.30
ATOM
842
C
GLN
G
258
102.259
−136.706
128.194
1.00
101.52
ATOM
843
O
GLN
G
258
102.841
−137.083
127.180
1.00
101.61
ATOM
844
CB
GLN
G
258
102.879
−134.899
129.807
1.00
102.03
ATOM
845
CG
GLN
G
258
102.869
−133.420
130.152
1.00
104.23
ATOM
846
CD
GLN
G
258
103.675
−133.098
131.394
1.00
105.40
ATOM
847
OE1
GLN
G
258
103.500
−133.721
132.440
1.00
106.32
ATOM
848
NE2
GLN
G
258
104.560
−132.114
131.286
1.00
107.50
ATOM
849
N
LEU
G
259
101.713
−137.546
129.068
1.00
101.69
ATOM
850
CA
LEU
G
259
101.768
−138.993
128.881
1.00
102.17
ATOM
851
C
LEU
G
259
100.423
−139.538
128.414
1.00
102.41
ATOM
852
O
LEU
G
259
99.373
−139.022
128.788
1.00
102.52
ATOM
853
CB
LEU
G
259
102.160
−139.681
130.196
1.00
101.92
ATOM
854
CG
LEU
G
259
103.530
−139.358
130.810
1.00
101.73
ATOM
855
CD1
LEU
G
259
103.500
−139.663
132.298
1.00
99.97
ATOM
856
CD2
LEU
G
259
104.617
−140.161
130.111
1.00
101.60
ATOM
857
N
LEU
G
260
100.465
−140.582
127.593
1.00
102.49
ATOM
858
CA
LEU
G
260
99.251
−141.217
127.088
1.00
102.67
ATOM
859
C
LEU
G
260
99.110
−142.568
127.778
1.00
103.61
ATOM
860
O
LEU
G
260
99.966
−143.437
127.621
1.00
103.69
ATOM
861
CB
LEU
G
260
99.353
−141.409
125.576
1.00
101.68
ATOM
862
CG
LEU
G
260
99.448
−140.122
124.752
1.00
101.95
ATOM
863
CD1
LEU
G
260
99.953
−140.434
123.355
1.00
104.05
ATOM
864
CD2
LEU
G
260
98.086
−139.457
124.703
1.00
102.22
ATOM
865
N
LEU
G
261
98.030
−142.748
128.533
1.00
105.17
ATOM
866
CA
LEU
G
261
97.815
−143.991
129.276
1.00
106.41
ATOM
867
C
LEU
G
261
96.661
−144.836
128.744
1.00
107.21
ATOM
868
O
LEU
G
261
95.708
−144.314
128.167
1.00
106.94
ATOM
869
CB
LEU
G
261
97.549
−143.661
130.743
1.00
105.72
ATOM
870
CG
LEU
G
261
98.232
−142.392
131.272
1.00
104.79
ATOM
871
CD1
LEU
G
261
97.660
−142.057
132.637
1.00
105.02
ATOM
872
CD2
LEU
G
261
99.741
−142.577
131.340
1.00
103.55
ATOM
873
N
ASN
G
262
96.752
−146.147
128.959
1.00
108.66
ATOM
874
CA
ASN
G
262
95.724
−147.091
128.515
1.00
110.01
ATOM
875
C
ASN
G
262
95.280
−146.877
127.074
1.00
112.35
ATOM
876
O
ASN
G
262
94.183
−146.376
126.822
1.00
113.39
ATOM
877
CB
ASN
G
262
94.502
−147.021
129.432
1.00
108.26
ATOM
878
CG
ASN
G
262
94.817
−147.452
130.846
1.00
107.34
ATOM
879
OD1
ASN
G
262
95.692
−148.294
131.054
1.00
106.57
ATOM
880
ND2
ASN
G
262
94.093
−146.901
131.819
1.00
107.98
ATOM
881
N
GLY
G
263
96.129
−147.276
126.132
1.00
114.75
ATOM
882
CA
GLY
G
263
95.801
−147.115
124.728
1.00
117.52
ATOM
883
C
GLY
G
263
96.326
−148.237
123.856
1.00
119.64
ATOM
884
O
GLY
G
263
96.747
−149.284
124.354
1.00
119.72
ATOM
885
N
SER
G
264
96.308
−148.008
122.547
1.00
121.07
ATOM
886
CA
SER
G
264
96.771
−148.992
121.578
1.00
122.04
ATOM
887
C
SER
G
264
98.291
−149.038
121.482
1.00
123.78
ATOM
888
O
SER
G
264
98.949
−148.003
121.362
1.00
123.31
ATOM
889
CB
SER
G
264
96.178
−148.678
120.201
1.00
120.42
ATOM
890
OG
SER
G
264
96.593
−149.632
119.242
1.00
120.43
ATOM
891
N
LEU
G
265
98.844
−150.244
121.540
1.00
126.40
ATOM
892
CA
LEU
G
265
100.286
−150.421
121.448
1.00
129.15
ATOM
893
C
LEU
G
265
100.693
−150.823
120.037
1.00
130.72
ATOM
894
O
LEU
G
265
99.983
−151.573
119.368
1.00
130.95
ATOM
895
CB
LEU
G
265
100.764
−151.493
122.433
1.00
130.79
ATOM
896
CG
LEU
G
265
100.641
−151.191
123.929
1.00
132.07
ATOM
897
CD1
LEU
G
265
99.572
−152.079
124.562
1.00
132.65
ATOM
898
CD2
LEU
G
265
101.988
−151.433
124.590
1.00
131.38
ATOM
899
N
ALA
G
266
101.838
−150.322
119.586
1.00
132.23
ATOM
900
CA
ALA
G
266
102.339
−150.651
118.259
1.00
134.12
ATOM
901
C
ALA
G
266
102.910
−152.065
118.269
1.00
135.84
ATOM
902
O
ALA
G
266
103.783
−152.381
119.077
1.00
136.72
ATOM
903
CB
ALA
G
266
103.413
−149.656
117.848
1.00
133.87
ATOM
904
N
GLU
G
267
102.417
−152.911
117.370
1.00
137.31
ATOM
905
CA
GLU
G
267
102.878
−154.294
117.286
1.00
138.28
ATOM
906
C
GLU
G
267
104.287
−154.420
116.704
1.00
138.43
ATOM
907
O
GLU
G
267
104.941
−155.449
116.877
1.00
138.51
ATOM
908
CB
GLU
G
267
101.913
−155.128
116.435
1.00
139.08
ATOM
909
CG
GLU
G
267
101.055
−156.140
117.199
1.00
140.98
ATOM
910
CD
GLU
G
267
100.029
−155.491
118.109
1.00
142.29
ATOM
911
OE1
GLU
G
267
100.397
−155.083
119:230
1.00
143.33
ATOM
912
OE2
GLU
G
267
98.855
−155.381
117.696
1.00
142.39
ATOM
913
N
GLU
G
268
104.752
−153.384
116.011
1.00
138.17
ATOM
914
CA
GLU
G
268
106.084
−153.414
115.408
1.00
137.57
ATOM
915
C
GLU
G
268
107.102
−152.595
116.197
1.00
136.57
ATOM
916
O
GLU
G
268
107.669
−153.080
117.175
1.00
135.78
ATOM
917
CB
GLU
G
268
106.017
−152.915
113.959
1.00
137.43
ATOM
918
CG
GLU
G
268
105.211
−153.810
113.019
1.00
137.50
ATOM
919
CD
GLU
G
268
105.925
−155.107
112.673
1.00
136.95
ATOM
920
OE1
GLU
G
268
106.938
−155.053
111.943
1.00
136.48
ATOM
921
OE2
GLU
G
268
105.474
−156.178
113.133
1.00
135.94
ATOM
922
N
GLU
G
269
107.332
−151.358
115.767
1.00
136.24
ATOM
923
CA
GLU
G
269
108.289
−150.478
116.434
1.00
135.49
ATOM
924
C
GLU
G
269
107.654
−149.157
116.855
1.00
134.06
ATOM
925
O
GLU
G
269
106.488
−148.888
116.558
1.00
133.72
ATOM
926
CB
GLU
G
269
109.470
−150.193
115.500
1.00
136.19
ATOM
927
CG
GLU
G
269
110.272
−151.422
115.099
1.00
136.58
ATOM
928
CD
GLU
G
269
111.252
−151.862
116.170
1.00
136.55
ATOM
929
OE1
GLU
G
269
112.182
−151.086
116.479
1.00
136.08
ATOM
930
OE2
GLU
G
269
111.095
−152.982
116.700
1.00
136.04
ATOM
931
N
VAL
G
270
108.431
−148.335
117.553
1.00
132.32
ATOM
932
CA
VAL
G
270
107.958
−147.031
117.994
1.00
130.76
ATOM
933
C
VAL
G
270
107.775
−146.124
116.783
1.00
129.81
ATOM
934
O
VAL
G
270
108.685
−145.973
115.968
1.00
130.00
ATOM
935
CB
VAL
G
270
108.966
−146.377
118.966
1.00
131.35
ATOM
936
CG1
VAL
O
270
108.937
−144.860
118.811
1.00
131.66
ATOM
937
CG2
VAL
G
270
108.621
−146.755
120.395
1.00
130.81
ATOM
938
N
VAL
G
271
106.598
−145.520
116.668
1.00
128.20
ATOM
939
CA
VAL
G
271
106.313
−144.636
115.547
1.00
126.00
ATOM
940
C
VAL
G
271
105.937
−143.226
115.975
1.00
123.76
ATOM
941
O
VAL
G
271
104.888
−143.009
116.581
1.00
123.89
ATOM
942
CB
VAL
G
271
105.168
−145.198
114.680
1.00
127.31
ATOM
943
CG1
VAL
G
271
105.713
−146.225
113.699
1.00
127.47
ATOM
944
CG2
VAL
G
271
104.117
−145.838
115.573
1.00
128.06
ATOM
945
N
ILE
G
272
106.804
−142.272
115.656
1.00
121.03
ATOM
946
CA
ILE
G
272
106.572
−140.872
115.990
1.00
118.57
ATOM
947
C
ILE
G
272
105.975
−140.139
114.795
1.00
116.72
ATOM
948
O
ILE
G
272
106.352
−140.394
113.652
1.00
116.74
ATOM
949
CB
ILE
G
272
107.887
−140.177
116.415
1.00
118.70
ATOM
950
CG1
ILE
G
272
109.042
−140.617
115.512
1.00
119.92
ATOM
951
CG2
ILE
G
272
108.203
−140.507
117.860
1.00
118.21
ATOM
952
CD1
ILE
G
272
109.082
−139.944
114.157
1.00
120.90
ATOM
953
N
ARG
G
273
105.040
−139.232
115.052
1.00
114.52
ATOM
954
CA
ARG
G
273
104.405
−138.500
113.967
1.00
112.62
ATOM
955
C
ARG
G
273
103.923
−137.100
114.334
1.00
112.88
ATOM
956
O
ARG
G
273
103.487
−136.845
115.455
1.00
113.04
ATOM
957
CB
ARG
G
273
103.254
−139.339
113.401
1.00
110.31
ATOM
958
CG
ARG
G
273
102.587
−140.260
114.417
1.00
106.44
ATOM
959
CD
ARG
G
273
102.311
−141.625
113.795
1.00
104.49
ATOM
960
NE
ARG
G
273
101.683
−142.560
114.726
1.00
102.80
ATOM
961
CZ
ARG
G
273
101.400
−143.826
114.433
1.00
101.53
ATOM
962
NH1
ARG
G
273
101.691
−144.310
113.234
1.00
99.91
ATOM
963
NH2
ARG
G
273
100.825
−144.607
115.337
1.00
100.38
ATOM
964
N
SER
G
274
104.018
−136.199
113.363
1.00
113.32
ATOM
965
CA
SER
G
274
103.618
−134.810
113.531
1.00
114.33
ATOM
966
C
SER
G
274
103.131
−134.296
112.184
1.00
115.69
ATOM
967
O
SER
G
274
103.519
−134.816
111.140
1.00
115.97
ATOM
968
CB
SER
G
274
104.814
−133.974
114.003
1.00
114.12
ATOM
969
OG
SER
G
274
104.457
−132.617
114.198
1.00
114.92
ATOM
970
N
ASP
G
275
102.285
−133.274
112.205
1.00
117.50
ATOM
971
CA
ASP
G
275
101.764
−132.718
110.966
1.00
119.82
ATOM
972
C
ASP
G
275
102.906
−132.161
110.109
1.00
122.54
ATOM
973
O
ASP
G
275
102.898
−132.283
108.885
1.00
123.77
ATOM
974
CB
ASP
G
275
100.742
−131.626
111.284
1.00
119.48
ATOM
975
CG
ASP
G
275
99.978
−131.168
110.059
1.00
119.15
ATOM
976
OD1
ASP
G
275
100.457
−130.241
109.380
1.00
119.47
ATOM
977
OD2
ASP
G
275
98.907
−131.748
109.774
1.00
119.52
ATOM
978
N
ASN
G
276
103.885
−131.547
110.766
1.00
124.54
ATOM
979
CA
ASN
G
276
105.053
−130.984
110.095
1.00
126.17
ATOM
980
C
ASN
G
276
106.182
−130.957
111.116
1.00
126.16
ATOM
981
O
ASN
G
276
106.209
−130.097
111.996
1.00
127.07
ATOM
982
CB
ASN
G
276
104.764
−129.565
109.575
1.00
127.69
ATOM
983
CG
ASN
G
276
105.951
−128.957
108.826
1.00
130.48
ATOM
984
OD1
ASN
G
276
106.983
−128.684
109.436
1.00
131.45
ATOM
985
ND2
ASN
G
276
105.817
−128.752
107.512
1.00
133.41
ATOM
986
N
PHE
G
277
107.098
−131.915
111.001
1.00
125.51
ATOM
987
CA
PHE
G
277
108.223
−132.013
111.917
1.00
124.73
ATOM
988
C
PHE
G
277
109.164
−130.820
111.885
1.00
124.32
ATOM
989
O
PHE
G
277
109.851
−130.543
112.869
1.00
124.52
ATOM
990
CB
PHE
G
277
109.021
−133.282
111.645
1.00
124.97
ATOM
991
CG
PHE
G
277
108.616
−134.440
112.498
1.00
124.70
ATOM
992
CD1
PHE
G
277
107.662
−135.352
112.061
1.00
124.33
ATOM
993
CD2
PHE
G
277
109.177
−134.606
113.758
1.00
125.19
ATOM
994
CE1
PHE
G
277
107.274
−136.416
112.872
1.00
124.54
ATOM
995
CE2
PHE
G
277
108.797
−135.661
114.575
1.00
125.18
ATOM
996
CZ
PHE
G
277
107.843
−136.568
114.132
1.00
124.26
ATOM
997
N
THR
G
278
109.205
−130.113
110.763
1.00
123.74
ATOM
998
CA
THR
G
278
110.082
−126.954
110.660
1.00
123.33
ATOM
999
C
THR
G
278
109.545
−127.821
111.522
1.00
122.48
ATOM
1000
O
THR
G
278
110.298
−126.961
111.974
1.00
122.37
ATOM
1001
CB
THR
G
278
110.194
−128.471
109.208
1.00
123.77
ATOM
1002
OG1
THR
G
278
110.512
−129.583
108.363
1.00
122.39
ATOM
1003
CG2
THR
G
278
111.299
−127.432
109.076
1.00
124.71
ATOM
1004
N
ASN
G
279
108.237
−127.836
111.752
1.00
121.41
ATOM
1005
CA
ASN
G
279
107.588
−126.823
112.569
1.00
120.64
ATOM
1006
C
ASN
G
279
107.553
−127.290
114.019
1.00
119.86
ATOM
1007
O
ASN
G
279
107.075
−128.384
114.316
1.00
119.77
ATOM
1008
CB
ASN
G
279
106.168
−126.570
112.060
1.00
122.36
ATOM
1009
CG
ASN
G
279
105.527
−125.362
112.703
1.00
123.19
ATOM
1010
OD1
ASN
G
279
106.104
−124.276
112.716
1.00
124.95
ATOM
1011
ND2
ASN
G
279
104.322
−125.540
113.228
1.00
123.66
ATOM
1012
N
ASN
G
280
108.059
−126.451
114.917
1.00
118.87
ATOM
1013
CA
ASN
G
280
108.107
−126.780
116.336
1.00
118.01
ATOM
1014
C
ASN
G
280
106.785
−126.592
117.075
1.00
117.08
ATOM
1015
O
ASN
G
280
106.615
−127.104
118.181
1.00
117.55
ATOM
1016
CB
ASN
G
280
109.187
−125.943
117.019
1.00
118.90
ATOM
1017
CG
ASN
G
280
109.006
−124.457
116.781
1.00
119.84
ATOM
1018
OD1
ASN
G
280
108.992
−124.001
115.638
1.00
119.58
ATOM
1019
ND2
ASN
G
280
108.865
−123.694
117.859
1.00
121.00
ATOM
1020
N
ALA
G
281
105.851
−125.862
116.472
1.00
115.19
ATOM
1021
CA
ALA
G
281
104.557
−125.612
117.102
1.00
112.13
ATOM
1022
C
ALA
G
281
103.663
−126.842
117.077
1.00
109.69
ATOM
1023
O
ALA
G
281
102.802
−127.010
117.937
1.00
109.86
ATOM
1024
CB
ALA
G
281
103.859
−124.453
116.409
1.00
113.29
ATOM
1025
N
LYS
G
282
103.865
−127.693
116.078
1.00
106.77
ATOM
1026
CA
LYS
G
282
103.078
−128.911
115.939
1.00
104.34
ATOM
1027
C
LYS
G
282
103.510
−129.937
116.979
1.00
102.27
ATOM
1028
O
LYS
G
282
104.699
−130.197
117.147
1.00
101.74
ATOM
1029
CB
LYS
G
282
103.260
−129.495
114.534
1.00
104.78
ATOM
1030
CG
LYS
G
282
102.841
−128.579
113.392
1.00
105.16
ATOM
1031
CD
LYS
G
282
101.326
−128.507
113.226
1.00
107.10
ATOM
1032
CE
LYS
G
282
100.956
−127.757
111.947
1.00
107.70
ATOM
1033
NZ
LYS
G
282
99.493
−127.777
111.657
1.00
108.40
ATOM
1034
N
THR
G
283
102.542
−130.523
117.671
1.00
100.94
ATOM
1035
CA
THR
G
283
102.848
−131.514
118.693
1.00
100.59
ATOM
1036
C
THR
G
283
103.256
−132.850
118.076
1.00
99.16
ATOM
1037
O
THR
G
283
102.777
−133.227
117.003
1.00
98.27
ATOM
1038
CB
THR
G
283
101.643
−131.751
119.620
1.00
102.18
ATOM
1039
OG1
THR
G
283
100.523
−132.185
118.843
1.00
103.66
ATOM
1040
CG2
THR
G
283
101.276
−130.478
120.352
1.00
102.55
ATOM
1041
N
ILE
G
284
104.135
−133.567
118.767
1.00
97.96
ATOM
1042
CA
ILE
G
284
104.616
−134.855
118.292
1.00
97.14
ATOM
1043
C
ILE
G
284
104.064
−136.005
119.123
1.00
97.31
ATOM
1044
O
ILE
G
284
104.344
−136.110
120.318
1.00
97.07
ATOM
1045
CB
ILE
G
284
106.157
−134.899
118.331
1.00
96.52
ATOM
1046
CG1
ILE
G
284
106.714
−133.841
117.375
1.00
96.20
ATOM
1047
CG2
ILE
G
284
106.656
−136.293
117.964
1.00
96.59
ATOM
1048
CD1
ILE
G
284
108.195
−133.608
117.509
1.00
96.44
ATOM
1049
N
ILE
G
285
103.276
−136.863
118.485
1.00
98.01
ATOM
1050
CA
ILE
G
285
102.685
−138.013
119.158
1.00
99.80
ATOM
1051
C
ILE
G
285
103.602
−139.229
119.071
1.00
101.17
ATOM
1052
O
ILE
G
285
103.975
−139.661
117.980
1.00
100.52
ATOM
1053
CB
ILE
G
285
101.312
−138.386
118.537
1.00
99.80
ATOM
1054
CG1
ILE
G
285
100.246
−137.372
118.961
1.00
100.25
ATOM
1055
CG2
ILE
G
285
100.903
−139.782
118.977
1.00
100.16
ATOM
1056
CD1
ILE
G
285
100.455
−135.980
118.409
1.00
102.53
ATOM
1057
N
VAL
G
286
103.955
−139.782
120.224
1.00
103.62
ATOM
1058
CA
VAL
G
286
104.831
−140.943
120.282
1.00
106.86
ATOM
1059
C
VAL
G
286
104.055
−142.192
120.683
1.00
109.26
ATOM
1060
O
VAL
G
286
103.311
−142.176
121.663
1.00
109.45
ATOM
1061
CB
VAL
G
286
105.953
−140.727
121.314
1.00
107.59
ATOM
1062
CG1
VAL
G
286
106.960
−141.865
121.236
1.00
108.43
ATOM
1063
CG2
VAL
G
286
106.621
−139.385
121.074
1.00
107.25
ATOM
1064
N
GLN
G
287
104.222
−143.270
119.923
1.00
112.10
ATOM
1065
CA
GLN
G
287
103.540
−144.527
120.225
1.00
115.20
ATOM
1066
C
GLN
G
287
104.575
−145.549
120.675
1.00
116.64
ATOM
1067
O
GLN
G
287
105.564
−145.779
119.982
1.00
117.12
ATOM
1068
CB
GLN
G
287
102.803
−145.057
118.992
1.00
116.06
ATOM
1069
CG
GLN
G
287
101.378
−145.514
119.275
1.00
117.17
ATOM
1070
CD
GLN
G
287
100.932
−146.653
118.378
1.00
117.46
ATOM
1071
OE1
GLN
G
287
101.086
−146.600
117.158
1.00
116.74
ATOM
1072
NE2
GLN
G
287
100.366
−147.692
118.984
1.00
117.73
ATOM
1073
N
LEU
G
288
104.338
−146.170
121.825
1.00
119.08
ATOM
1074
CA
LEU
G
288
105.270
−147.150
122.375
1.00
122.20
ATOM
1075
C
LEU
G
288
104.788
−148.588
122.203
1.00
124.20
ATOM
1076
O
LEU
G
288
103.594
−148.867
122.309
1.00
124.85
ATOM
1077
CB
LEU
G
288
105.479
−146.874
123.862
1.00
121.50
ATOM
1078
CG
LEU
G
288
105.844
−145.433
124.231
1.00
121.43
ATOM
1079
CD1
LEU
G
288
105.637
−145.233
125.720
1.00
122.39
ATOM
1080
CD2
LEU
G
288
107.281
−145.134
123.832
1.00
123.19
ATOM
1081
N
LYS
G
289
105.721
−149.503
121.953
1.00
126.07
ATOM
1082
CA
LYS
G
289
105.380
−150.912
121.782
1.00
127.42
ATOM
1083
C
LYS
G
289
105.478
−151.682
123.097
1.00
127.68
ATOM
1084
O
LYS
G
289
104.856
−152.732
123.258
1.00
126.88
ATOM
1085
CB
LYS
G
289
106.285
−151.552
120.723
1.00
128.03
ATOM
1086
CG
LYS
G
289
107.441
−150.673
120.252
1.00
129.35
ATOM
1087
CD
LYS
G
289
108.782
−151.209
120.736
1.00
130.44
ATOM
1088
CE
LYS
G
289
109.966
−150.519
120.051
1.00
130.23
ATOM
1089
NZ
LYS
G
289
110.464
−149.301
120.754
1.00
131.22
ATOM
1090
N
GLU
G
290
106.263
−151.159
124.033
1.00
128.43
ATOM
1091
CA
GLU
G
290
106.416
−151.788
125.341
1.00
128.96
ATOM
1092
C
GLU
G
290
105.619
−150.998
126.375
1.00
127.87
ATOM
1093
O
GLU
G
290
105.837
−149.800
126.553
1.00
127.30
ATOM
1094
CB
GLU
G
290
107.894
−151.843
125.744
1.00
131.22
ATOM
1095
CG
GLU
G
290
108.714
−152.872
124.974
1.00
134.12
ATOM
1096
CD
GLU
G
290
110.117
−153.047
125.532
1.00
135.56
ATOM
1097
OE1
GLU
G
290
110.924
−152.097
125.442
1.00
136.25
ATOM
1098
OE2
GLU
G
290
110.412
−154.138
126.064
1.00
135.63
ATOM
1099
N
SER
G
291
104.697
−151.673
127.052
1.00
126.04
ATOM
1100
CA
SER
G
291
103.856
−151.030
128.053
1.00
124.60
ATOM
1101
C
SER
G
291
104.589
−150.693
129.344
1.00
124.35
ATOM
1102
O
SER
G
291
105.113
−151.577
130.025
1.00
125.69
ATOM
1103
CB
SER
G
291
102.656
−151.922
128.379
1.00
123.78
ATOM
1104
OG
SER
G
291
103.084
−153.161
128.915
1.00
123.88
ATOM
1105
N
VAL
G
292
104.615
−149.408
129.679
1.00
123.16
ATOM
1106
CA
VAL
G
292
105.263
−148.941
130.898
1.00
121.87
ATOM
1107
C
VAL
G
292
104.192
−148.750
131.968
1.00
121.23
ATOM
1108
O
VAL
G
292
103.399
−147.813
131.897
1.00
120.89
ATOM
1109
CB
VAL
G
292
105.968
−147.595
130.662
1.00
121.78
ATOM
1110
CG1
VAL
G
292
106.742
−147.191
131.907
1.00
121.71
ATOM
1111
CG2
VAL
G
292
106.886
−147.697
129.461
1.00
120.71
ATOM
1112
N
GLU
G
293
104.169
−149.640
132.952
1.00
120.89
ATOM
1113
CA
GLU
G
293
103.178
−149.574
134.015
1.00
121.29
ATOM
1114
C
GLU
G
293
103.474
−148.476
135.031
1.00
121.55
ATOM
1115
O
GLU
G
293
104.568
−148.408
135.591
1.00
121.80
ATOM
1116
CB
GLU
G
293
103.086
−150.933
134.723
1.00
121.08
ATOM
1117
CG
GLU
G
293
102.116
−150.988
135.893
1.00
121.19
ATOM
1118
CD
GLU
G
293
101.966
−152.394
136.445
1.00
122.13
ATOM
1119
OE1
GLU
G
293
102.946
−153.167
136.371
1.00
122.07
ATOM
1120
OE2
GLU
G
293
100.876
−152.722
136.961
1.00
123.25
ATOM
1121
N
ILE
G
294
102.493
−147.610
135.258
1.00
121.87
ATOM
1122
CA
ILE
G
294
102.637
−146.524
136.217
1.00
121.70
ATOM
1123
C
ILE
G
294
101.621
−146.720
137.333
1.00
121.42
ATOM
1124
O
ILE
G
294
100.433
−146.917
137.076
1.00
121.27
ATOM
1125
CB
ILE
G
294
102.418
−145.160
135.536
1.00
122.02
ATOM
1126
CG1
ILE
G
294
102.578
−144.033
136.557
1.00
122.87
ATOM
1127
CG2
ILE
G
294
101.048
−145.125
134.884
1.00
121.44
ATOM
1128
CD1
ILE
G
294
102.714
−142.660
135.931
1.00
122.60
ATOM
1129
N
ASN
G
295
102.097
−146.674
138.573
1.00
121.00
ATOM
1130
CA
ASN
G
295
101.238
−146.874
139.736
1.00
121.44
ATOM
1131
C
ASN
G
295
101.204
−145.674
140.677
1.00
121.01
ATOM
1132
O
ASN
G
295
102.134
−145.462
141.457
1.00
121.03
ATOM
1133
CB
ASN
G
295
101.710
−148.103
140.517
1.00
122.74
ATOM
1134
CG
ASN
G
295
101.810
−149.344
139.651
1.00
122.92
ATOM
1135
OD1
ASN
G
295
100.819
−149.793
139.075
1.00
122.88
ATOM
1136
ND2
ASN
G
295
103.011
−149.905
139.555
1.00
122.92
ATOM
1137
N
CYS
G
296
100.124
−144.901
140.605
1.00
120.25
ATOM
1138
CA
CYS
G
296
99.960
−143.728
141.456
1.00
118.86
ATOM
1139
C
CYS
G
296
98.928
−144.045
142.537
1.00
117.99
ATOM
1140
O
CYS
G
296
97.835
−144.528
142.236
1.00
117.00
ATOM
1141
CB
CYS
G
296
99.466
−142.537
140.636
1.00
119.34
ATOM
1142
SG
CYS
G
296
100.316
−142.227
139.052
1.00
119.64
ATOM
1143
N
THR
G
297
99.268
−143.765
143.791
1.00
117.75
ATOM
1144
CA
THR
G
297
98.356
−144.042
144.895
1.00
117.96
ATOM
1145
C
THR
G
297
98.386
−142.956
145.967
1.00
117.03
ATOM
1146
O
THR
G
297
99.224
−142.055
145.933
1.00
115.96
ATOM
1147
CB
THR
G
297
98.692
−145.394
145.560
1.00
118.94
ATOM
1148
OG1
THR
G
297
99.992
−145.325
146.159
1.00
120.18
ATOM
1149
CG2
THR
G
297
98.688
−146.509
144.524
1.00
119.76
ATOM
1150
N
ARG
G
298
97.459
−143.050
146.916
1.00
116.66
ATOM
1151
CA
ARG
G
298
97.369
−142.092
148.010
1.00
116.73
ATOM
1152
C
ARG
G
298
96.753
−142.780
149.228
1.00
118.95
ATOM
1153
O
ARG
G
298
95.710
−143.426
149.124
1.00
118.61
ATOM
1154
CB
ARG
G
298
96.521
−140.888
147.585
1.00
114.49
ATOM
1155
CG
ARG
G
298
96.550
−139.720
148.564
1.00
112.45
ATOM
1156
CD
ARG
G
298
95.473
−139.831
149.632
1.00
110.20
ATOM
1157
NE
ARG
G
298
94.138
−139.603
149.085
1.00
108.71
ATOM
1158
CZ
ARG
G
298
93.026
−139.566
149.812
1.00
107.87
ATOM
1159
NH1
ARG
G
298
93.082
−139.742
151.125
1.00
107.98
ATOM
1160
NH2
ARG
G
298
91.857
−139.349
149.227
1.00
107.62
ATOM
1161
N
PRO
G
299
97.402
−142.651
150.399
1.00
121.18
ATOM
1162
CA
PRO
G
299
96.984
−143.233
151.681
1.00
123.48
ATOM
1163
C
PRO
G
299
95.484
−143.182
151.977
1.00
125.98
ATOM
1164
O
PRO
G
299
94.700
−142.658
151.186
1.00
126.15
ATOM
1165
CB
PRO
G
299
97.805
−142.442
152.691
1.00
123.50
ATOM
1166
CG
PRO
G
299
99.092
−142.253
151.958
1.00
122.94
ATOM
1167
CD
PRO
G
299
98.621
−141.841
150.576
1.00
121.50
ATOM
1168
N
ASN
G
300
95.092
−143.724
153.127
1.00
127.96
ATOM
1169
CA
ASN
G
300
93.684
−143.752
153.502
1.00
130.21
ATOM
1170
C
ASN
G
300
93.364
−143.237
154.905
1.00
131.51
ATOM
1171
O
ASN
G
300
93.985
−142.292
155.394
1.00
131.18
ATOM
1172
CB
ASN
G
300
93.137
−145.173
153.341
1.00
130.07
ATOM
1173
CG
ASN
G
300
93.919
−146.194
154.142
1.00
130.57
ATOM
1174
OD1
ASN
G
300
95.139
−146.299
154.015
1.00
130.10
ATOM
1175
ND2
ASN
G
300
93.216
−146.958
154.969
1.00
131.18
ATOM
1176
N
GLN
G
301
92.384
−143.877
155.537
1.00
133.80
ATOM
1177
CA
GLN
G
301
91.912
−143.514
156.871
1.00
135.82
ATOM
1178
C
GLN
G
301
92.716
−144.156
158.004
1.00
137.01
ATOM
1179
O
GLN
G
301
92.448
−143.903
159.180
1.00
136.35
ATOM
1180
CB
GLN
G
301
90.436
−143.911
157.001
1.00
135.35
ATOM
1181
CG
GLN
G
301
89.724
−143.404
158.248
1.00
135.28
ATOM
1182
CD
GLN
G
301
89.563
−141.897
158.258
1.00
134.83
ATOM
1183
OE1
GLN
G
301
89.785
−141.230
157.247
1.00
134.19
ATOM
1184
NE2
GLN
G
301
89.160
−141.353
159.402
1.00
133.96
ATOM
1185
N
ASN
G
302
93.701
−144.979
157.656
1.00
138.83
ATOM
1186
CA
ASN
G
302
94.522
−145.651
158.662
1.00
140.81
ATOM
1187
C
ASN
G
302
95.302
−144.706
159.574
1.00
141.45
ATOM
1188
O
ASN
G
302
96.112
−145.155
160.387
1.00
141.13
ATOM
1189
CB
ASN
G
302
95.494
−146.633
157.997
1.00
141.80
ATOM
1190
CG
ASN
G
302
94.851
−147.975
157.690
1.00
143.04
ATOM
1191
OD1
ASN
G
302
94.307
−148.632
158.579
1.00
142.23
ATOM
1192
ND2
ASN
G
302
94.919
−148.392
156.431
1.00
142.70
ATOM
1193
N
THR
G
303
95.063
−143.404
159.440
1.00
142.24
ATOM
1194
CA
THR
G
303
95.745
−142.423
160.278
1.00
142.95
ATOM
1195
C
THR
G
303
95.430
−142.755
161.734
1.00
143.18
ATOM
1196
O
THR
G
303
96.274
−143.285
162.457
1.00
143.28
ATOM
1197
CB
THR
G
303
95.263
−140.990
159.969
1.00
143.28
ATOM
1198
OG1
THR
G
303
95.502
−140.691
158.588
1.00
143.23
ATOM
1199
CG2
THR
G
303
96.006
−139.980
160.831
1.00
144.01
ATOM
1200
N
ARG
G
304
94.208
−142.441
162.154
1.00
143.39
ATOM
1201
CA
ARG
G
304
93.762
−142.731
163.512
1.00
143.68
ATOM
1202
C
ARG
G
304
92.770
−143.886
163.431
1.00
143.18
ATOM
1203
O
ARG
G
304
92.051
−144.019
162.441
1.00
143.86
ATOM
1204
CB
ARG
G
304
93.108
−141.495
164.138
1.00
144.11
ATOM
1205
CG
ARG
G
304
94.084
−140.349
164.381
1.00
145.32
ATOM
1206
CD
ARG
G
304
95.261
−140.809
165.238
1.00
147.31
ATOM
1207
NE
ARG
G
304
96.271
−139.770
165.421
1.00
147.56
ATOM
1208
CZ
ARG
G
304
97.419
−139.953
166.067
1.00
147.68
ATOM
1209
NH1
ARG
G
304
97.706
−141.136
166.593
1.00
146.72
ATOM
1210
NH2
ARG
G
304
98.283
−138.953
166.187
1.00
146.63
ATOM
1211
N
LYS
G
305
92.728
−144.722
164.464
1.00
141.97
ATOM
1212
CA
LYS
G
305
91.836
−145.874
164.442
1.00
140.98
ATOM
1213
C
LYS
G
305
90.851
−145.964
165.606
1.00
140.38
ATOM
1214
O
LYS
G
305
89.921
−146.771
165.565
1.00
140.91
ATOM
1215
CB
LYS
G
305
92.668
−147.159
164.384
1.00
141.00
ATOM
1216
CG
LYS
G
305
91.930
−148.361
163.818
1.00
140.99
ATOM
1217
CD
LYS
G
305
91.633
−148.169
162.338
1.00
141.06
ATOM
1218
CE
LYS
G
305
90.967
−149.397
161.741
1.00
141.85
ATOM
1219
NZ
LYS
G
305
90.730
−149.243
160.279
1.00
140.37
ATOM
1220
N
SER
G
306
91.042
−145.149
166.638
1.00
139.15
ATOM
1221
CA
SER
G
306
90.143
−145.193
167.788
1.00
137.47
ATOM
1222
C
SER
G
306
89.922
−143.845
168.466
1.00
136.43
ATOM
1223
O
SER
G
306
90.820
−143.005
168.518
1.00
136.13
ATOM
1224
CB
SER
G
306
90.663
−146.198
168.818
1.00
137.39
ATOM
1225
OG
SER
G
306
90.732
−147.502
168.267
1.00
136.71
ATOM
1226
N
ILE
G
307
88.713
−143.654
168.985
1.00
135.40
ATOM
1227
CA
ILE
G
307
88.345
−142.424
169.678
1.00
135.12
ATOM
1228
C
ILE
G
307
87.998
−142.771
171.124
1.00
133.50
ATOM
1229
O
ILE
G
307
87.697
−143.924
171.433
1.00
133.64
ATOM
1230
CB
ILE
G
307
87.122
−141.754
169.013
1.00
135.24
ATOM
1231
CG1
ILE
G
307
87.410
−141.505
167.531
1.00
136.04
ATOM
1232
CG2
ILE
G
307
86.802
−140.437
169.709
1.00
135.56
ATOM
1233
CD1
ILE
G
307
86.248
−140.899
166.770
1.00
137.26
ATOM
1234
N
HIS
G
308
88.042
−141.777
172.005
1.00
132.91
ATOM
1235
CA
HIS
G
308
87.739
−141.997
173.416
1.00
132.86
ATOM
1236
C
HIS
G
308
86.709
−141.003
173.946
1.00
130.36
ATOM
1237
O
HIS
G
308
86.915
−139.791
173.887
1.00
130.34
ATOM
1238
CB
HIS
G
308
89.023
−141.899
174.244
1.00
133.35
ATOM
1239
CG
HIS
G
308
90.081
−142.878
173.836
1.00
134.57
ATOM
1240
ND1
HIS
G
308
90.588
−142.935
172.557
1.00
135.10
ATOM
1241
CD2
HIS
G
308
90.726
−143.837
174.541
1.00
134.82
ATOM
1242
CE1
HIS
G
308
91.501
−143.889
172.490
1.00
135.21
ATOM
1243
NE2
HIS
G
308
91.604
−144.451
173.680
1.00
134.93
ATOM
1244
N
ILE
G
309
85.593
−141.524
174.451
1.00
129.66
ATOM
1245
CA
ILE
G
309
84.535
−140.678
174.996
1.00
132.96
ATOM
1246
C
ILE
G
309
84.853
−140.335
176.442
1.00
129.06
ATOM
1247
O
ILE
G
309
85.368
−141.163
177.189
1.00
130.20
ATOM
1248
CB
ILE
G
309
83.150
−141.381
174.982
1.00
129.80
ATOM
1249
CG1
ILE
G
309
82.794
−141.842
173.567
1.00
129.99
ATOM
1250
CG2
ILE
G
309
82.079
−140.427
175.513
1.00
129.45
ATOM
1251
CD1
ILE
G
309
82.707
−140.721
172.551
1.00
131.16
ATOM
1252
N
AGLY
G
312
84.519
−139.106
176.817
0.50
130.34
ATOM
1253
N
BGLY
G
312
84.580
−139.093
176.821
0.50
130.54
ATOM
1254
CA
AGLY
G
312
84.745
−138.635
178.168
0.50
130.62
ATOM
1255
CA
BGLY
G
312
84.870
−138.668
178.175
0.50
132.03
ATOM
1256
C
AGLY
G
312
83.667
−137.629
178.521
0.50
130.49
ATOM
1257
C
BGLY
G
312
84.057
−137.472
178.615
0.50
132.56
ATOM
1258
O
AGLY
G
312
83.395
−136.719
177.734
0.50
129.55
ATOM
1259
O
BGLY
G
312
83.971
−136.469
177.901
0.50
132.01
ATOM
1260
N
APRO
G
313
83.028
−137.767
179.695
0.50
130.44
ATOM
1261
N
BPRO
G
313
83.443
−137.553
179.805
0.50
133.04
ATOM
1262
CA
APRO
G
313
81.972
−136.840
180.115
0.50
131.53
ATOM
1263
CA
BPRO
G
313
82.628
−136.463
180.344
0.50
134.04
ATOM
1264
C
APRO
G
313
82.413
−135.375
180.098
0.50
132.66
ATOM
1265
C
BPRO
G
313
83.434
−135.170
180.483
0.50
134.58
ATOM
1266
O
APRO
G
313
81.581
−134.468
180.030
0.50
132.16
ATOM
1267
O
BPRO
G
313
84.184
−134.985
181.445
0.50
133.93
ATOM
1268
CB
APRO
G
313
81.618
−137.333
181.522
0.50
130.68
ATOM
1269
CB
BPRO
G
313
82.148
−137.021
181.686
0.50
133.44
ATOM
1270
CG
APRO
G
313
82.890
−137.969
181.999
0.50
130.40
ATOM
1271
CG
BPRO
G
313
83.237
−137.955
182.081
0.50
133.35
ATOM
1272
CD
APRO
G
313
83.349
−138.718
180.774
0.50
130.35
ATOM
1273
CD
BPRO
G
313
83.569
−138.649
180.783
0.50
133.12
ATOM
1274
N
AGLY
G
314
83.726
−135.158
180.147
0.50
133.78
ATOM
1275
N
BGLY
G
314
83.279
−134.282
179.508
0.50
135.23
ATOM
1276
CA
AGLY
G
314
84.259
−133.808
180.140
0.50
135.11
ATOM
1277
CA
BGLY
G
314
84.005
−133.028
179.539
0.50
136.68
ATOM
1278
C
AGLY
G
314
85.185
−133.514
178.973
0.50
136.46
ATOM
1279
C
BGLY
G
314
85.217
−133.071
178.633
0.50
137.64
ATOM
1280
O
AGLY
G
314
85.779
−132.436
178.916
0.50
136.65
ATOM
1281
O
BGLY
G
314
86.040
−132.151
178.641
0.50
137.68
ATOM
1282
N
AARG
G
315
85.317
−134.464
178.047
0.50
137.71
ATOM
1283
N
BARG
G
315
85.330
−134.146
177.855
0.50
138.87
ATOM
1284
CA
AARG
G
315
86.179
−134.280
176.881
0.50
138.32
ATOM
1285
CA
BARG
G
315
86.445
−134.302
176.934
0.50
139.12
ATOM
1286
C
AARG
G
315
86.103
−135.394
175.835
0.50
139.46
ATOM
1287
C
BARG
G
315
86.339
−135.478
175.969
0.50
140.02
ATOM
1288
O
AARG
G
315
85.308
−136.326
175.960
0.50
140.02
ATOM
1289
O
BARG
G
315
85.746
−136.513
176.268
0.50
140.48
ATOM
1290
CB
AARG
G
315
87.634
−134.069
177.327
0.50
138.97
ATOM
1291
CB
BARG
G
315
87.766
−134.388
177.707
0.50
140.03
ATOM
1292
CG
AARG
G
315
88.095
−134.926
178.501
0.50
138.68
ATOM
1293
CG
BARG
G
315
87.860
−135.517
178.714
0.50
140.27
ATOM
1294
CD
AARG
G
315
89.381
−134.354
179.103
0.50
138.38
ATOM
1295
CD
BARG
G
315
89.207
−135.465
179.420
0.50
140.88
ATOM
1296
NE
AARG
G
315
89.824
−135.078
180.294
0.50
138.70
ATOM
1297
NE
BARG
G
315
89.349
−136.496
180.445
0.50
140.22
ATOM
1298
CZ
AARG
G
315
90.845
−134.703
181.062
0.50
138.42
ATOM
1299
CZ
BARG
G
315
90.422
−136.637
181.219
0.50
139.80
ATOM
1300
NH1
AARG
G
315
91.530
−133.607
180.768
0.50
138.28
ATOM
1301
NH1
BARG
G
315
91.454
−135.813
181.085
0.50
138.98
ATOM
1302
NH2
AARG
G
315
91.181
−135.424
182.125
0.50
138.35
ATOM
1303
NH2
BARG
G
315
90.466
−137.604
182.126
0.50
138.56
ATOM
1304
N
ALA
G
316
86.934
−135.273
174.800
1.00
144.80
ATOM
1305
CA
ALA
G
316
86.989
−136.226
173.690
1.00
143.79
ATOM
1306
C
ALA
G
316
88.432
−136.339
173.191
1.00
146.46
ATOM
1307
O
ALA
G
316
89.285
−135.522
173.549
1.00
147.07
ATOM
1308
CB
ALA
G
316
86.065
−135.774
172.553
1.00
144.31
ATOM
1309
N
PHE
G
317
88.701
−137.350
172.366
1.00
149.66
ATOM
1310
CA
PHE
G
317
90.048
−137.578
171.852
1.00
151.88
ATOM
1311
C
PHE
G
317
90.071
−137.825
170.343
1.00
152.98
ATOM
1312
O
PHE
G
317
89.095
−138.305
169.765
1.00
153.44
ATOM
1313
CB
PHE
G
317
90.693
−138.774
172.565
1.00
151.95
ATOM
1314
CG
PHE
G
317
90.978
−138.541
174.025
1.00
152.25
ATOM
1315
CD1
PHE
G
317
89.940
−138.387
174.940
1.00
151.95
ATOM
1316
CD2
PHE
G
317
92.290
−138.486
174.487
1.00
152.28
ATOM
1317
CE1
PHE
G
317
90.204
−138.181
176.293
1.00
151.79
ATOM
1318
CE2
PHE
G
317
92.565
−138.281
175.838
1.00
152.38
ATOM
1319
CZ
PHE
G
317
91.519
−138.129
176.742
1.00
152.23
ATOM
1320
N
TYR
G
318
91.199
−137.492
169.720
1.00
154.53
ATOM
1321
CA
TYR
G
318
91.406
−137.676
168.283
1.00
155.71
ATOM
1322
C
TYR
G
318
90.427
−136.911
167.391
1.00
155.64
ATOM
1323
O
TYR
G
318
89.646
−137.520
166.659
1.00
155.52
ATOM
1324
CB
TYR
G
318
91.340
−139.165
167.919
1.00
156.48
ATOM
1325
CG
TYR
G
318
92.267
−140.063
168.711
1.00
157.82
ATOM
1326
CD1
TYR
G
318
92.044
−140.309
170.065
1.00
158.34
ATOM
1327
CD2
TYR
G
318
93.353
−140.689
168.099
1.00
158.59
ATOM
1328
CE1
TYR
G
318
92.875
−141.159
170.791
1.00
158.85
ATOM
1329
CE2
TYR
G
318
94.192
−141.542
168.817
1.00
159.15
ATOM
1330
CZ
TYR
G
318
93.945
−141.772
170.162
1.00
159.22
ATOM
1331
OH
TYR
G
318
94.765
−142.615
170.877
1.00
159.77
ATOM
1332
N
THR
G
319
90.474
−135.583
167.440
1.00
155.30
ATOM
1333
CA
THR
G
319
89.589
−134.763
166.616
1.00
155.09
ATOM
1334
C
THR
G
319
90.251
−133.430
166.269
1.00
154.62
ATOM
1335
O
THR
G
319
89.683
−132.611
165.545
1.00
153.91
ATOM
1336
CB
THR
G
319
88.246
−134.485
167.334
1.00
155.83
ATOM
1337
OG1
THR
G
319
87.669
−135.722
167.771
1.00
156.26
ATOM
1338
CG2
THR
G
319
87.265
−133.797
166.389
1.00
155.64
ATOM
1339
N
THR
G
320
91.460
−133.223
166.783
1.00
154.50
ATOM
1340
CA
THR
G
320
92.199
−131.990
166.532
1.00
154.03
ATOM
1341
C
THR
G
320
93.278
−132.162
165.463
1.00
153.67
ATOM
1342
O
THR
G
320
94.420
−131.734
165.646
1.00
153.56
ATOM
1343
CB
THR
G
320
92.867
−131.467
167.823
1.00
154.73
ATOM
1344
OG1
THR
G
320
93.762
−132.462
168.338
1.00
154.90
ATOM
1345
CG2
THR
G
320
91.814
−131.143
168.874
1.00
154.48
ATOM
1346
N
GLY
G
321
92.912
−132.791
164.350
1.00
152.75
ATOM
1347
CA
GLY
G
321
93.861
−132.995
163.270
1.00
151.08
ATOM
1348
C
GLY
G
321
94.014
−131.729
162.449
1.00
150.38
ATOM
1349
O
GLY
G
321
93.119
−131.365
161.685
1.00
149.77
ATOM
1350
N
GLU
G
322
95.150
−131.056
162.605
1.00
149.39
ATOM
1351
CA
GLU
G
322
95.405
−129.814
161.884
1.00
148.29
ATOM
1352
C
GLU
G
322
96.649
−129.909
161.008
1.00
147.73
ATOM
1353
O
GLU
G
322
96.564
−130.249
159.827
1.00
146.53
ATOM
1354
CB
GLU
G
322
95.572
−128.662
162.877
1.00
148.27
ATOM
1355
CG
GLU
G
322
94.503
−128.616
163.956
1.00
148.79
ATOM
1356
CD
GLU
G
322
94.707
−127.471
164.928
1.00
148.76
ATOM
1357
OE1
GLU
G
322
95.819
−127.354
165.485
1.00
148.26
ATOM
1358
OE2
GLU
G
322
93.753
−126.693
165.138
1.00
148.68
ATOM
1359
N
ILE
G
322A
97.801
−129.607
161.603
1.00
147.61
ATOM
1360
CA
ILE
G
322A
99.087
−129.634
160.910
1.00
147.08
ATOM
1361
C
ILE
G
322A
98.968
−129.223
159.444
1.00
146.30
ATOM
1362
O
ILE
G
322A
98.978
−130.067
158.548
1.00
145.89
ATOM
1363
CB
ILE
G
322A
99.755
−131.036
161.003
1.00
147.76
ATOM
1364
CG1
ILE
G
322A
98.807
−132.120
160.480
1.00
148.35
ATOM
1365
CG2
ILE
G
322A
100.149
−131.324
162.446
1.00
147.20
ATOM
1366
CD1
ILE
G
322A
99.408
−133.513
160.469
1.00
146.09
ATOM
1367
N
ILE
G
323
98.854
−127.917
159.214
1.00
145.42
ATOM
1368
CA
ILE
G
323
98.728
−127.370
157.865
1.00
144.18
ATOM
1369
C
ILE
G
323
99.759
−127.991
156.928
1.00
143.58
ATOM
1370
O
ILE
G
323
100.878
−127.492
156.799
1.00
143.84
ATOM
1371
CB
ILE
G
323
98.919
−125.833
157.864
1.00
143.68
ATOM
1372
CG1
ILE
G
323
97.919
−125.179
158.823
1.00
142.95
ATOM
1373
CG2
ILE
G
323
98.743
−125.285
156.452
1.00
142.76
ATOM
1374
CD1
ILE
G
323
96.462
−125.431
158.476
1.00
141.08
ATOM
1375
N
GLY
G
324
99.371
−129.082
156.275
1.00
142.21
ATOM
1376
CA
GLY
G
324
100.273
−129.759
155.363
1.00
139.77
ATOM
1377
C
GLY
G
324
99.607
−130.172
154.067
1.00
137.92
ATOM
1378
O
GLY
G
324
98.645
−129.543
153.622
1.00
137.70
ATOM
1379
N
ASP
G
325
100.119
−131.238
153.461
1.00
136.00
ATOM
1380
CA
ASP
G
325
99.579
−131.735
152.203
1.00
133.50
ATOM
1381
C
ASP
G
325
98.873
−133.076
152.378
1.00
131.01
ATOM
1382
O
ASP
G
325
99.517
−134.125
152.420
1.00
130.01
ATOM
1383
CB
ASP
G
325
100.701
−131.883
151.168
1.00
134.89
ATOM
1384
CG
ASP
G
325
101.463
−130.587
150.937
1.00
135.71
ATOM
1385
OD1
ASP
G
325
100.829
−129.577
150.563
1.00
136.06
ATOM
1386
OD2
ASP
G
325
102.698
−130.580
151.125
1.00
134.58
ATOM
1387
N
ILE
G
326
97.549
−133.035
152.488
1.00
129.15
ATOM
1388
CA
ILE
G
326
96.752
−134.248
152.636
1.00
127.17
ATOM
1389
C
ILE
G
326
96.181
−134.612
151.270
1.00
125.06
ATOM
1390
O
ILE
G
326
95.556
−135.660
151.097
1.00
123.58
ATOM
1391
CB
ILE
G
326
95.585
−134.060
153.642
1.00
128.41
ATOM
1392
CG1
ILE
G
326
94.645
−132.942
153.173
1.00
129.82
ATOM
1393
CG2
ILE
G
326
96.140
−133.766
155.028
1.00
127.42
ATOM
1394
CD1
ILE
G
326
95.235
−131.542
153.236
1.00
130.42
ATOM
1395
N
ARG
G
327
96.405
−133.725
150.305
1.00
123.14
ATOM
1396
CA
ARG
G
327
95.941
−133.924
148.939
1.00
121.11
ATOM
1397
C
ARG
G
327
97.147
−134.327
148.100
1.00
120.61
ATOM
1398
O
ARG
G
327
97.188
−134.076
146.897
1.00
120.79
ATOM
1399
CB
ARG
G
327
95.358
−132.627
148.372
1.00
120.85
ATOM
1400
CG
ARG
G
327
94.459
−131.843
149.317
1.00
118.55
ATOM
1401
CD
ARG
G
327
93.929
−130.592
148.622
1.00
116.19
ATOM
1402
NE
ARG
G
327
93.320
−129.641
149.549
1.00
114.20
ATOM
1403
CZ
ARG
G
327
92.253
−129.896
150.299
1.00
112.97
ATOM
1404
NH1
ARG
G
327
91.661
−131.080
150.241
1.00
112.39
ATOM
1405
NH2
ARG
G
327
91.777
−128.963
151.111
1.00
111.25
ATOM
1406
N
GLN
G
328
98.134
−134.943
148.743
1.00
120.56
ATOM
1407
CA
GLN
G
328
99.349
−135.363
148.056
1.00
120.47
ATOM
1408
C
GLN
G
328
99.300
−136.818
147.602
1.00
120.52
ATOM
1409
O
GLN
G
328
98.731
−137.676
148.278
1.00
119.31
ATOM
1410
CB
GLN
G
328
100.564
−135.158
148.965
1.00
120.86
ATOM
1411
CG
GLN
G
328
101.888
−135.560
148.330
1.00
121.32
ATOM
1412
CD
GLN
G
328
103.053
−135.494
149.302
1.00
121.93
ATOM
1413
OE1
GLN
G
328
104.192
−135.792
148.942
1.00
121.20
ATOM
1414
NE2
GLN
G
328
102.771
−135.104
150.541
1.00
121.27
ATOM
1415
N
ALA
G
329
99.909
−137.081
146.451
1.00
120.97
ATOM
1416
CA
ALA
G
329
99.961
−138.422
145.883
1.00
121.52
ATOM
1417
C
ALA
G
329
101.311
−138.622
145.204
1.00
122.43
ATOM
1418
O
ALA
G
329
102.079
−137.673
145.043
1.00
122.38
ATOM
1419
CB
ALA
G
329
98.836
−138.606
144.877
1.00
121.15
ATOM
1420
N
HIS
G
330
101.600
−139.858
144.811
1.00
123.54
ATOM
1421
CA
HIS
G
330
102.861
−140.168
144.150
1.00
124.36
ATOM
1422
C
HIS
G
330
102.701
−141.357
143.210
1.00
124.92
ATOM
1423
O
HIS
G
330
101.851
−142.221
143.431
1.00
124.23
ATOM
1424
CB
HIS
G
330
103.943
−140.473
145.189
1.00
124.54
ATOM
1425
CG
HIS
G
330
103.653
−141.680
146.028
1.00
125.33
ATOM
1426
ND1
HIS
G
330
102.556
−141.764
146.858
1.00
125.66
ATOM
1427
CD2
HIS
G
330
104.317
−142.852
146.162
1.00
125.46
ATOM
1428
CE1
HIS
G
330
102.556
−142.937
147.467
1.00
125.67
ATOM
1429
NE2
HIS
G
330
103.614
−143.617
147.061
1.00
125.50
ATOM
1430
N
CYS
G
331
103.519
−141.392
142.162
1.00
125.98
ATOM
1431
CA
CYS
G
331
103.471
−142.479
141.187
1.00
127.16
ATOM
1432
C
CYS
G
331
104.763
−143.292
141.212
1.00
129.17
ATOM
1433
O
CYS
G
331
105.756
−142.883
141.814
1.00
129.56
ATOM
1434
CB
CYS
G
331
103.263
−141.931
139.777
1.00
124.83
ATOM
1435
SG
CYS
G
331
101.784
−140.903
139.514
1.00
121.39
ATOM
1436
N
ASN
G
332
104.744
−144.441
140.542
1.00
131.21
ATOM
1437
CA
ASN
G
332
105.907
−145.317
140.491
1.00
133.03
ATOM
1438
C
ASN
G
332
106.019
−146.059
139.161
1.00
132.94
ATOM
1439
O
ASN
G
332
105.054
−146.665
138.696
1.00
133.74
ATOM
1440
CB
ASN
G
332
105.845
−146.346
141.625
1.00
135.06
ATOM
1441
CG
ASN
G
332
106.883
−146.090
142.699
1.00
138.61
ATOM
1442
OD1
ASN
G
332
108.036
−145.797
142.379
1.00
140.34
ATOM
1443
ND2
ASN
G
332
106.492
−146.199
143.969
1.00
141.14
ATOM
1444
N
ILE
G
333
107.205
−146.016
138.562
1.00
132.27
ATOM
1445
CA
ILE
G
333
107.458
−146.705
137.305
1.00
131.40
ATOM
1446
C
ILE
G
333
108.827
−147.371
137.344
1.00
131.17
ATOM
1447
O
ILE
G
333
109.685
−146.991
138.138
1.00
130.59
ATOM
1448
CB
ILE
G
333
107.438
−145.738
136.110
1.00
130.99
ATOM
1449
CG1
ILE
G
333
108.336
−144.541
136.416
1.00
131.41
ATOM
1450
CG2
ILE
G
333
106.013
−145.321
135.796
1.00
130.08
ATOM
1451
CD1
ILE
G
333
108.808
−143.797
135.194
1.00
130.71
ATOM
1452
N
SER
G
334
109.027
−148.362
136.482
1.00
130.80
ATOM
1453
CA
SER
G
334
110.298
−149.071
136.417
1.00
130.47
ATOM
1454
C
SER
G
334
111.379
−148.202
135.781
1.00
129.18
ATOM
1455
O
SER
G
334
111.253
−147.785
134.630
1.00
128.30
ATOM
1456
CB
SER
G
334
110.137
−150.366
135.620
1.00
131.53
ATOM
1457
OG
SER
G
334
109.185
−151.224
136.226
1.00
134.33
ATOM
1458
N
ARG
G
335
112.441
−147.938
136.537
1.00
128.40
ATOM
1459
CA
ARG
G
335
113.550
−147.114
136.062
1.00
127.88
ATOM
1460
C
ARG
G
335
114.232
−147.713
134.831
1.00
127.39
ATOM
1461
O
ARG
G
335
114.594
−146.992
133.901
1.00
125.90
ATOM
1462
CB
ARG
G
335
114.588
−146.944
137.174
1.00
128.63
ATOM
1463
CG
ARG
G
335
115.721
−145.986
136.839
1.00
130.03
ATOM
1464
CD
ARG
G
335
115.354
−144.549
137.175
1.00
131.46
ATOM
1465
NE
ARG
G
335
116.464
−143.631
136.927
1.00
133.64
ATOM
1466
CZ
ARG
G
335
116.796
−143.164
135.728
1.00
135.08
ATOM
1467
NH1
ARG
G
335
116.102
−143.521
134.655
1.00
135.62
ATOM
1468
NH2
ARG
G
335
117.828
−142.340
135.600
1.00
136.66
ATOM
1469
N
ALA
G
336
114.409
−149.030
134.831
1.00
127.56
ATOM
1470
CA
ALA
G
336
115.060
−149.712
133.717
1.00
127.56
ATOM
1471
C
ALA
G
336
114.193
−149.726
132.462
1.00
127.53
ATOM
1472
O
ALA
G
336
114.702
−149.613
131.347
1.00
127.19
ATOM
1473
CB
ALA
G
336
115.419
−151.140
134.121
1.00
127.32
ATOM
1474
N
LYS
G
337
112.884
−149.870
132.653
1.00
127.34
ATOM
1475
CA
LYS
G
337
111.929
−149.897
131.547
1.00
126.12
ATOM
1476
C
LYS
G
337
111.697
−148.511
130.952
1.00
125.19
ATOM
1477
O
LYS
G
337
111.525
−148.370
129.742
1.00
125.25
ATOM
1478
CB
LYS
G
337
110.590
−150.483
132.019
1.00
125.26
ATOM
1479
CG
LYS
G
337
110.486
−152.006
131.948
1.00
125.56
ATOM
1480
CD
LYS
G
337
110.195
−152.482
130.524
1.00
125.22
ATOM
1481
CE
LYS
G
337
110.096
−154.003
130.442
1.00
125.33
ATOM
1482
NZ
LYS
G
337
109.878
−154.486
129.045
1.00
122.70
ATOM
1483
N
TRP
G
338
111.693
−147.488
131.802
1.00
123.88
ATOM
1484
CA
TRP
G
338
111.471
−146.120
131.343
1.00
122.35
ATOM
1485
C
TRP
G
338
112.656
−145.584
130.551
1.00
122.08
ATOM
1486
O
TRP
G
338
112.482
−144.934
129.521
1.00
121.22
ATOM
1487
CB
TRP
G
338
111.188
−145.199
132.535
1.00
121.06
ATOM
1488
CG
TRP
G
338
111.092
−143.744
132.172
1.00
119.31
ATOM
1489
CD1
TRP
G
338
111.853
−142.726
132.669
1.00
119.14
ATOM
1490
CD2
TRP
G
338
110.185
−143.145
131.235
1.00
118.77
ATOM
1491
NE1
TRP
G
338
111.479
−141.531
132.103
1.00
119.01
ATOM
1492
CE2
TRP
G
338
110.458
−141.758
131.220
1.00
118.35
ATOM
1493
CE3
TRP
G
338
109.170
−143.644
130.409
1.00
118.58
ATOM
1494
CZ2
TRP
G
338
109.751
−140.864
130.408
1.00
117.90
ATOM
1495
CZ3
TRP
G
338
108.467
−142.753
129.601
1.00
118.02
ATOM
1496
CH2
TRP
G
338
108.763
−141.378
129.609
1.00
117.53
ATOM
1497
N
ASN
G
339
113.860
−145.865
131.034
1.00
122.65
ATOM
1498
CA
ASN
G
339
115.068
−145.399
130.367
1.00
123.64
ATOM
1499
C
ASN
G
339
115.247
−146.081
129.015
1.00
122.72
ATOM
1500
O
ASN
G
339
115.779
−145.490
128.079
1.00
120.87
ATOM
1501
CB
ASN
G
339
116.292
−145.661
131.249
1.00
126.14
ATOM
1502
CG
ASN
G
339
117.430
−144.705
130.960
1.00
128.79
ATOM
1503
OD1
ASN
G
339
117.338
−143.511
131.247
1.00
129.26
ATOM
1504
ND2
ASN
G
339
118.508
−145.223
130.384
1.00
130.45
ATOM
1505
N
ASP
G
340
114.805
−147.331
128.922
1.00
122.55
ATOM
1506
CA
ASP
G
340
114.913
−148.080
127.676
1.00
122.48
ATOM
1507
C
ASP
G
340
113.925
−147.552
126.654
1.00
121.75
ATOM
1508
O
ASP
G
340
114.254
−147.398
125.482
1.00
121.24
ATOM
1509
CB
ASP
G
340
114.651
−149.569
127.913
1.00
123.36
ATOM
1510
CG
ASP
G
340
115.932
−150.373
128.021
1.00
124.46
ATOM
1511
OD1
ASP
G
340
116.606
−150.547
126.987
1.00
124.57
ATOM
1512
OD2
ASP
G
340
116.263
−150.820
129.138
1.00
124.24
ATOM
1513
N
THR
G
341
112.709
−147.277
127.107
1.00
121.23
ATOM
1514
CA
THR
G
341
111.678
−146.760
126.223
1.00
120.37
ATOM
1515
C
THR
G
341
112.005
−145.321
125.864
1.00
120.04
ATOM
1516
O
THR
G
341
111.571
−144.813
124.833
1.00
119.85
ATOM
1517
CB
THR
G
341
110.292
−146.798
126.885
1.00
119.50
ATOM
1518
OG1
THR
G
341
110.387
−146.310
128.227
1.00
118.81
ATOM
1519
CG2
THR
G
341
109.738
−148.202
126.892
1.00
119.32
ATOM
1520
N
LEU
G
342
112.780
−144.668
126.719
1.00
118.58
ATOM
1521
CA
LEU
G
342
113.172
−143.285
126.488
1.00
117.21
ATOM
1522
C
LEU
G
342
114.214
−143.283
125.372
1.00
117.06
ATOM
1523
O
LEU
G
342
114.277
−142.363
124.557
1.00
116.61
ATOM
1524
CB
LEU
G
342
113.757
−142.700
127.780
1.00
116.17
ATOM
1525
CG
LEU
G
342
113.453
−141.242
128.147
1.00
115.99
ATOM
1526
CD1
LEU
G
342
113.803
−141.014
129.608
1.00
115.86
ATOM
1527
CD2
LEU
G
342
114.230
−140.299
127.247
1.00
115.38
ATOM
1528
N
LYS
G
343
115.021
−144.340
125.341
1.00
117.43
ATOM
1529
CA
LYS
G
343
116.071
−144.497
124.340
1.00
117.14
ATOM
1530
C
LYS
G
343
115.481
−144.739
122.957
1.00
116.27
ATOM
1531
O
LYS
G
343
115.931
−144.159
121.970
1.00
114.89
ATOM
1532
CB
LYS
G
343
116.988
−145.668
124.720
1.00
118.24
ATOM
1533
CG
LYS
G
343
118.124
−145.916
123.741
1.00
119.11
ATOM
1534
CD
LYS
G
343
118.999
−147.081
124.184
1.00
118.05
ATOM
1535
CE
LYS
G
343
120.143
−147.321
123.205
1.00
117.07
ATOM
1536
NZ
LYS
G
343
121.015
−148.456
123.624
1.00
118.22
ATOM
1537
N
GLN
G
344
114.466
−145.594
122.890
1.00
115.18
ATOM
1538
CA
GLN
G
344
113.828
−145.899
121.617
1.00
114.37
ATOM
1539
C
GLN
G
344
113.146
−144.685
121.009
1.00
114.01
ATOM
1540
O
GLN
G
344
112.888
−144.642
119.807
1.00
113.70
ATOM
1541
CB
GLN
G
344
112.838
−147.051
121.780
1.00
113.68
ATOM
1542
CG
GLN
G
344
113.519
−148.414
121.728
1.00
114.75
ATOM
1543
CD
GLN
G
344
113.191
−149.300
122.912
1.00
115.83
ATOM
1544
OE1
GLN
G
344
112.072
−149.795
123.044
1.00
116.37
ATOM
1545
NE2
GLN
G
344
114.172
−149.505
123.784
1.00
116.57
ATOM
1546
N
ILE
G
345
112.858
−143.694
121.839
1.00
113.81
ATOM
1547
CA
ILE
G
345
112.241
−142.472
121.349
1.00
113.74
ATOM
1548
C
ILE
G
345
113.341
−141.701
120.641
1.00
114.51
ATOM
1549
O
ILE
G
345
113.143
−141.157
119.555
1.00
114.50
ATOM
1550
CB
ILE
G
345
111.689
−141.630
122.513
1.00
113.46
ATOM
1551
CG1
ILE
G
345
110.481
−142.345
123.133
1.00
113.45
ATOM
1552
CG2
ILE
G
345
111.291
−140.246
122.018
1.00
112.53
ATOM
1553
CD1
ILE
G
345
109.980
−141.716
124.407
1.00
114.16
ATOM
1554
N
VAL
G
346
114.509
−141.680
121.271
1.00
115.23
ATOM
1555
CA
VAL
G
346
115.670
−140.996
120.729
1.00
116.13
ATOM
1556
C
VAL
G
346
116.128
−141.657
119.439
1.00
116.56
ATOM
1557
O
VAL
G
346
116.491
−140.980
118.476
1.00
115.69
ATOM
1558
CB
VAL
G
346
116.836
−141.021
121.727
1.00
116.71
ATOM
1559
CG1
VAL
G
346
118.063
−140.394
121.104
1.00
116.76
ATOM
1560
CG2
VAL
G
346
116.444
−140.284
122.999
1.00
117.56
ATOM
1561
N
ILE
G
347
116.105
−142.984
119.423
1.00
116.67
ATOM
1562
CA
ILE
G
347
116.513
−143.735
118.246
1.00
117.05
ATOM
1563
C
ILE
G
347
115.693
−143.356
117.022
1.00
117.43
ATOM
1564
O
ILE
G
347
116.235
−143.207
115.928
1.00
117.11
ATOM
1565
CB
ILE
G
347
116.366
−145.248
118.488
1.00
118.09
ATOM
1566
CG1
ILE
G
347
117.391
−145.700
119.527
1.00
118.82
ATOM
1567
CG2
ILE
G
347
116.546
−146.012
117.186
1.00
117.63
ATOM
1568
CD1
ILE
G
347
118.828
−145.515
119.081
1.00
120.24
ATOM
1569
N
LYS
G
348
114.387
−143.199
117.215
1.00
118.10
ATOM
1570
CA
LYS
G
348
113.492
−142.836
116.125
1.00
119.28
ATOM
1571
C
LYS
G
348
113.477
−141.331
115.880
1.00
120.01
ATOM
1572
O
LYS
G
348
113.158
−140.883
114.780
1.00
119.90
ATOM
1573
CB
LYS
G
348
112.069
−143.326
116.416
1.00
119.85
ATOM
1574
CG
LYS
G
348
111.895
−144.844
116.394
1.00
120.97
ATOM
1575
CD
LYS
G
348
112.020
−145.410
114.980
1.00
122.36
ATOM
1576
CE
LYS
G
348
111.989
−146.937
114.982
1.00
123.02
ATOM
1577
NZ
LYS
G
348
112.225
−147.510
113.623
1.00
121.99
ATOM
1578
N
LEU
G
349
113.815
−140.550
116.903
1.00
120.97
ATOM
1579
CA
LEU
G
349
113.837
−139.098
116.757
1.00
122.27
ATOM
1580
C
LEU
G
349
115.045
−138.660
115.947
1.00
124.05
ATOM
1581
O
LEU
G
349
114.973
−137.710
115.170
1.00
124.00
ATOM
1582
CB
LEU
G
349
113.876
−138.406
118.122
1.00
121.94
ATOM
1583
CG
LEU
G
349
112.543
−138.095
118.810
1.00
122.12
ATOM
1584
CD1
LEU
G
349
112.808
−137.386
120.131
1.00
122.10
ATOM
1585
CD2
LEU
G
349
111.696
−137.209
117.900
1.00
122.34
ATOM
1586
N
ARG
G
350
116.161
−139.356
116.134
1.00
126.82
ATOM
1587
CA
ARG
G
350
117.382
−139.020
115.411
1.00
129.77
ATOM
1588
C
ARG
G
350
117.297
−139.583
114.004
1.00
130.79
ATOM
1589
O
ARG
G
350
118.100
−139.246
113.138
1.00
130.39
ATOM
1590
CB
ARG
G
350
118.618
−139.578
116.136
1.00
131.03
ATOM
1591
CG
ARG
G
350
118.728
−141.100
116.172
1.00
134.23
ATOM
1592
CD
ARG
G
350
119.545
−141.557
117.385
1.00
136.50
ATOM
1593
NE
ARG
G
350
120.947
−141.131
117.377
1.00
137.14
ATOM
1594
CZ
ARG
G
350
121.944
−141.836
116.849
1.00
137.25
ATOM
1595
NH1
ARG
G
350
121.700
−143.008
116.276
1.00
136.86
ATOM
1596
NH2
ARG
G
350
123.190
−141.381
116.914
1.00
136.51
ATOM
1597
N
GLU
G
351
116.307
−140.440
113.783
1.00
131.73
ATOM
1598
CA
GLU
G
351
116.108
−141.051
112.477
1.00
131.78
ATOM
1599
C
GLU
G
351
115.426
−140.024
111.574
1.00
131.64
ATOM
1600
O
GLU
G
351
115.425
−140.150
110.352
1.00
130.89
ATOM
1601
CB
GLU
G
351
115.250
−142.319
112.618
1.00
132.20
ATOM
1602
CG
GLU
G
351
115.735
−143.503
111.787
1.00
133.83
ATOM
1603
CD
GLU
G
351
114.933
−144.778
112.033
1.00
134.12
ATOM
1604
OE1
GLU
G
351
114.970
−145.303
113.165
1.00
133.27
ATOM
1605
OE2
GLU
G
351
114.267
−145.261
111.092
1.00
133.23
ATOM
1606
N
GLN
G
352
114.851
−138.998
112.197
1.00
131.55
ATOM
1607
CA
GLN
G
352
114.174
−137.930
111.469
1.00
131.20
ATOM
1608
C
GLN
G
352
115.029
−136.667
111.583
1.00
131.74
ATOM
1609
O
GLN
G
352
115.015
−135.810
110.703
1.00
131.22
ATOM
1610
CB
GLN
G
352
112.775
−137.684
112.055
1.00
129.40
ATOM
1611
CG
GLN
G
352
111.683
−137.483
111.010
1.00
128.29
ATOM
1612
CD
GLN
G
352
111.760
−136.141
110.302
1.00
128.13
ATOM
1613
OE1
GLN
G
352
111.325
−136.007
109.158
1.00
128.02
ATOM
1614
NE2
GLN
G
352
112.296
−135.137
110.986
1.00
127.02
ATOM
1615
N
PHE
G
353
115.781
−136.567
112.675
1.00
132.98
ATOM
1616
CA
PHE
G
353
116.654
−135.423
112.911
1.00
135.12
ATOM
1617
C
PHE
G
353
118.045
−135.862
113.357
1.00
136.10
ATOM
1618
O
PHE
G
353
118.362
−135.841
114.547
1.00
136.53
ATOM
1619
CB
PHE
G
353
116.054
−134.490
113.969
1.00
135.78
ATOM
1620
CG
PHE
G
353
114.963
−133.605
113.447
1.00
137.46
ATOM
1621
CD1
PHE
G
353
113.645
−133.786
113.853
1.00
137.80
ATOM
1622
CD2
PHE
G
353
115.255
−132.586
112.544
1.00
137.80
ATOM
1623
CE1
PHE
G
353
112.631
−132.963
113.365
1.00
138.59
ATOM
1624
CE2
PHE
G
353
114.249
−131.759
112.050
1.00
138.17
ATOM
1625
CZ
PHE
G
353
112.935
−131.948
112.461
1.00
138.87
ATOM
1626
N
GLU
G
354
118.871
−136.261
112.397
1.00
137.05
ATOM
1627
CA
GLU
G
354
120.224
−136.707
112.687
1.00
137.91
ATOM
1628
C
GLU
G
354
121.203
−135.540
112.616
1.00
137.70
ATOM
1629
O
GLU
G
354
120.881
−134.475
112.085
1.00
137.66
ATOM
1630
CB
GLU
G
354
120.615
−137.825
111.716
1.00
138.86
ATOM
1631
CG
GLU
G
354
121.921
−138.512
112.053
1.00
139.85
ATOM
1632
CD
GLU
G
354
122.022
−138.871
113.521
1.00
140.14
ATOM
1633
OE1
GLU
G
354
121.152
−139.618
114.017
1.00
140.78
ATOM
1634
OE2
GLU
G
354
122.976
−138.403
114.175
1.00
139.52
ATOM
1635
N
ASN
G
355
122.406
−135.754
113.142
1.00
137.40
ATOM
1636
CA
ASN
G
355
123.425
−134.703
113.192
1.00
136.85
ATOM
1637
C
ASN
G
355
122.937
−133.573
114.098
1.00
136.44
ATOM
1638
O
ASN
G
355
123.254
−132.412
113.913
1.00
137.04
ATOM
1639
CB
ASN
G
355
123.740
−134.195
111.776
1.00
136.54
ATOM
1640
CG
ASN
G
355
124.508
−135.220
110.949
1.00
135.79
ATOM
1641
OD1
ASN
G
355
124.035
−136.328
110.725
1.00
135.13
ATOM
1642
ND2
ASN
G
355
125.715
−134.853
110.514
1.00
135.21
ATOM
1643
N
LYS
G
357
122.152
−133.950
115.096
1.00
135.07
ATOM
1644
CA
LYS
G
357
121.606
−133.017
116.079
1.00
133.42
ATOM
1645
C
LYS
G
357
121.698
−133.716
117.421
1.00
131.94
ATOM
1646
O
LYS
G
357
121.977
−134.913
117.471
1.00
131.61
ATOM
1647
CB
LYS
G
357
120.137
−132.700
115.770
1.00
133.82
ATOM
1648
CG
LYS
G
357
119.862
−132.151
114.378
1.00
134.32
ATOM
1649
CD
LYS
G
357
119.821
−130.635
114.369
1.00
135.18
ATOM
1650
CE
LYS
G
357
119.478
−130.113
112.987
1.00
135.74
ATOM
1651
NZ
LYS
G
357
119.344
−128.636
112.997
1.00
135.57
ATOM
1652
N
THR
G
358
121.466
−132.974
118.499
1.00
130.25
ATOM
1653
CA
THR
G
358
121.499
−133.557
119.832
1.00
128.54
ATOM
1654
C
THR
G
358
120.142
−133.485
120.532
1.00
127.66
ATOM
1655
O
THR
G
358
119.636
−132.395
120.811
1.00
127.33
ATOM
1656
CB
THR
G
358
122.531
−132.868
120.749
1.00
127.87
ATOM
1657
OG1
THR
G
358
123.852
−133.126
120.269
1.00
127.40
ATOM
1658
CG2
THR
G
358
122.406
−133.397
122.167
1.00
127.41
ATOM
1659
N
ILE
G
359
119.558
−134.647
120.813
1.00
126.20
ATOM
1660
CA
ILE
G
359
118.258
−134.718
121.480
1.00
125.26
ATOM
1661
C
ILE
G
359
118.360
−134.591
123.005
1.00
124.58
ATOM
1662
O
ILE
G
359
118.904
−135.468
123.681
1.00
124.63
ATOM
1663
CB
ILE
G
359
117.528
−136.050
121.154
1.00
124.56
ATOM
1664
CG1
ILE
G
359
117.243
−136.142
119.654
1.00
124.71
ATOM
1665
CG2
ILE
G
359
116.212
−136.130
121.922
1.00
124.84
ATOM
1666
CD1
ILE
G
359
118.474
−136.371
118.804
1.00
124.99
ATOM
1667
N
VAL
G
360
117.816
−133.503
123.541
1.00
123.68
ATOM
1668
CA
VAL
G
360
117.841
−133.248
124.977
1.00
122.86
ATOM
1669
C
VAL
G
360
116.417
−133.181
125.520
1.00
122.77
ATOM
1670
O
VAL
G
360
115.532
−132.627
124.874
1.00
122.31
ATOM
1671
CB
VAL
G
360
118.535
−131.907
125.278
1.00
122.10
ATOM
1672
CG1
VAL
G
360
118.861
−131.806
126.759
1.00
121.81
ATOM
1673
CG2
VAL
G
360
119.783
−131.772
124.427
1.00
122.35
ATOM
1674
N
PHE
G
361
116.201
−133.746
126.702
1.00
122.89
ATOM
1675
CA
PHE
G
361
114.881
−133.744
127.323
1.00
122.88
ATOM
1676
C
PHE
G
361
114.852
−132.840
128.544
1.00
123.80
ATOM
1677
O
PHE
G
361
115.619
−133.024
129.490
1.00
124.18
ATOM
1678
CB
PHE
G
361
114.486
−135.169
127.705
1.00
121.54
ATOM
1679
CG
PHE
G
361
114.075
−136.008
126.536
1.00
120.64
ATOM
1680
CD1
PHE
G
361
112.802
−135.884
125.995
1.00
121.67
ATOM
1681
CD2
PHE
G
361
114.967
−136.901
125.954
1.00
120.34
ATOM
1682
CE1
PHE
G
361
112.419
−136.638
124.889
1.00
122.25
ATOM
1683
CE2
PHE
G
361
114.596
−137.660
124.847
1.00
120.52
ATOM
1684
CZ
PHE
G
361
113.319
−137.528
124.314
1.00
121.45
ATOM
1685
N
ASN
G
362
113.954
−131.864
128.516
1.00
124.73
ATOM
1686
CA
ASN
G
362
113.837
−130.906
129.602
1.00
125.55
ATOM
1687
C
ASN
G
362
112.401
−130.831
130.118
1.00
124.88
ATOM
1688
O
ASN
G
362
111.485
−131.370
129.499
1.00
124.87
ATOM
1689
CB
ASN
G
362
114.294
−129.537
129.097
1.00
127.19
ATOM
1690
CG
ASN
G
362
114.691
−128.608
130.215
1.00
130.61
ATOM
1691
OD1
ASN
G
362
113.874
−128.287
131.083
1.00
131.85
ATOM
1692
ND2
ASN
G
362
115.948
−128.168
130.199
1.00
133.40
ATOM
1693
N
HIS
G
363
112.207
−130.159
131.248
1.00
124.22
ATOM
1694
CA
HIS
G
363
110.878
−130.014
131.826
1.00
123.37
ATOM
1695
C
HIS
G
363
110.003
−129.081
130.986
1.00
122.33
ATOM
1696
O
HIS
G
363
110.445
−128.552
129.965
1.00
123.35
ATOM
1697
CB
HIS
G
363
110.986
−129.485
133.261
1.00
123.55
ATOM
1698
CG
HIS
G
363
111.789
−128.228
133.388
1.00
123.69
ATOM
1699
ND1
HIS
G
363
111.430
−127.051
132.769
1.00
123.31
ATOM
1700
CD2
HIS
G
363
112.933
−127.966
134.063
1.00
124.89
ATOM
1701
CE1
HIS
G
363
112.319
−126.118
133.056
1.00
123.86
ATOM
1702
NE2
HIS
G
363
113.242
−126.646
133.839
1.00
125.14
ATOM
1703
N
SER
G
364
108.763
−128.876
131.419
1.00
119.87
ATOM
1704
CA
SER
G
364
107.853
−128.002
130.691
1.00
117.00
ATOM
1705
C
SER
G
364
108.279
−126.547
130.857
1.00
115.19
ATOM
1706
O
SER
G
364
108.577
−126.102
131.964
1.00
115.16
ATOM
1707
CB
SER
G
364
106.422
−128.192
131.192
1.00
116.69
ATOM
1708
OG
SER
G
364
105.495
−127.562
130.324
1.00
116.92
ATOM
1709
N
SER
G
365
108.307
−125.811
129.752
1.00
113.25
ATOM
1710
CA
SER
G
365
108.711
−124.411
129.770
1.00
112.58
ATOM
1711
C
SER
G
365
107.797
−123.480
130.566
1.00
112.63
ATOM
1712
O
SER
G
365
108.216
−122.389
130.949
1.00
113.24
ATOM
1713
CB
SER
G
365
108.848
−123.897
128.341
1.00
112.43
ATOM
1714
OG
SER
G
365
107.754
−124.318
127.550
1.00
112.84
ATOM
1715
N
GLY
G
366
106.559
−123.895
130.823
1.00
112.08
ATOM
1716
CA
GLY
G
366
105.661
−123.044
131.591
1.00
111.71
ATOM
1717
C
GLY
G
366
104.224
−123.031
131.111
1.00
111.01
ATOM
1718
O
GLY
G
366
103.920
−123.550
130.041
1.00
111.21
ATOM
1719
N
GLY
G
367
103.339
−122.439
131.908
1.00
110.29
ATOM
1720
CA
GLY
G
367
101.935
−122.374
131.538
1.00
109.86
ATOM
1721
C
GLY
G
367
101.013
−122.876
132.633
1.00
109.09
ATOM
1722
O
GLY
G
367
101.382
−122.880
133.806
1.00
110.03
ATOM
1723
N
ASP
G
368
99.810
−123.300
132.255
1.00
107.77
ATOM
1724
CA
ASP
G
368
98.847
−123.813
133.219
1.00
106.93
ATOM
1725
C
ASP
G
368
99.347
−125.117
133.825
1.00
105.42
ATOM
1726
O
ASP
G
368
99.888
−125.969
133.122
1.00
105.22
ATOM
1727
CB
ASP
G
368
97.490
−124.046
132.551
1.00
109.08
ATOM
1728
CG
ASP
G
368
96.754
−122.749
132.246
1.00
110.72
ATOM
1729
OD1
ASP
G
368
96.346
−122.063
133.204
1.00
112.84
ATOM
1730
OD2
ASP
G
368
96.587
−122.420
131.052
1.00
110.53
ATOM
1731
N
PRO
G
369
99.161
−125.290
135.143
1.00
104.21
ATOM
1732
CA
PRO
G
369
99.587
−126.484
135.874
1.00
103.74
ATOM
1733
C
PRO
G
369
99.165
−127.797
135.227
1.00
102.96
ATOM
1734
O
PRO
G
369
99.756
−128.842
135.495
1.00
103.69
ATOM
1735
CB
PRO
G
369
98.955
−126.279
137.243
1.00
104.51
ATOM
1736
CG
PRO
G
369
99.051
−124.796
137.406
1.00
104.97
ATOM
1737
CD
PRO
G
369
98.530
−124.330
136.063
1.00
104.21
ATOM
1738
N
GLU
G
370
98.148
−127.745
134.376
1.00
101.68
ATOM
1739
CA
GLU
G
370
97.676
−128.949
133.707
1.00
100.29
ATOM
1740
C
GLU
G
370
98.665
−129.450
132.663
1.00
99.24
ATOM
1741
O
GLU
G
370
98.741
−130.650
132.396
1.00
100.20
ATOM
1742
CB
GLU
G
370
96.316
−128.699
133.049
1.00
101.70
ATOM
1743
CG
GLU
G
370
95.129
−128.747
134.007
1.00
101.29
ATOM
1744
CD
GLU
G
370
94.927
−127.459
134.790
1.00
101.71
ATOM
1745
OE1
GLU
G
370
94.058
−127.440
135.687
1.00
101.10
ATOM
1746
OE2
GLU
G
370
95.628
−126.465
134.508
1.00
102.45
ATOM
1747
N
ILE
G
371
99.424
−128.532
132.077
1.00
97.76
ATOM
1748
CA
ILE
G
371
100.401
−128.891
131.058
1.00
96.84
ATOM
1749
C
ILE
G
371
101.755
−129.144
131.702
1.00
95.29
ATOM
1750
O
ILE
G
371
102.455
−130.104
131.369
1.00
94.66
ATOM
1751
CB
ILE
G
371
100.563
−127.756
130.041
1.00
96.73
ATOM
1752
CG1
ILE
G
371
99.189
−127.193
129.678
1.00
96.23
ATOM
1753
CG2
ILE
G
371
101.254
−128.276
128.792
1.00
98.30
ATOM
1754
CD1
ILE
G
371
99.236
−125.769
129.192
1.00
96.31
ATOM
1755
N
VAL
G
372
102.111
−128.273
132.637
1.00
92.31
ATOM
1756
CA
VAL
G
372
103.376
−128.378
133.340
1.00
89.48
ATOM
1757
C
VAL
G
372
103.503
−129.702
134.081
1.00
87.73
ATOM
1758
O
VAL
G
372
104.586
−130.277
134.150
1.00
88.58
ATOM
1759
CB
VAL
G
372
103.533
−127.237
134.352
1.00
89.89
ATOM
1760
CG1
VAL
G
372
104.936
−127.246
134.926
1.00
91.74
ATOM
1761
CG2
VAL
G
372
103.233
−125.906
133.683
1.00
89.58
ATOM
1762
N
MET
G
373
102.395
−130.187
134.631
1.00
86.24
ATOM
1763
CA
MET
G
373
102.411
−131.444
135.364
1.00
86.32
ATOM
1764
C
MET
G
373
101.540
−132.498
134.689
1.00
86.85
ATOM
1765
O
MET
G
373
100.541
−132.174
134.051
1.00
86.82
ATOM
1766
CB
MET
G
373
101.930
−131.220
136.805
1.00
86.15
ATOM
1767
CG
MET
G
373
102.616
−130.059
137.512
1.00
85.92
ATOM
1768
SD
MET
G
373
103.120
−130.448
139.200
1.00
87.98
ATOM
1769
CE
MET
G
373
101.830
−129.658
140.161
1.00
88.57
ATOM
1770
N
HIS
G
374
101.930
−133.762
134.823
1.00
87.56
ATOM
1771
CA
HIS
G
374
101.161
−134.857
134.244
1.00
88.76
ATOM
1772
C
HIS
G
374
99.810
−134.931
134.944
1.00
90.65
ATOM
1773
O
HIS
G
374
99.699
−135.514
136.019
1.00
93.49
ATOM
1774
CB
HIS
G
374
101.905
−136.181
134.422
1.00
87.35
ATOM
1775
CG
HIS
G
374
101.079
−137.385
134.096
1.00
85.69
ATOM
1776
ND1
HIS
G
374
100.563
−137.614
132.839
1.00
85.77
ATOM
1777
CD2
HIS
G
374
100.677
−138.425
134.863
1.00
85.18
ATOM
1778
CE1
HIS
G
374
99.881
−138.745
132.845
1.00
87.31
ATOM
1779
NE2
HIS
G
374
99.934
−139.257
134.061
1.00
86.65
ATOM
1780
N
SER
G
375
98.788
−134.346
134.330
1.00
91.35
ATOM
1781
CA
SER
G
375
97.454
−134.327
134.918
1.00
91.01
ATOM
1782
C
SER
G
375
96.531
−135.438
134.431
1.00
90.01
ATOM
1783
O
SER
G
375
96.426
−135.685
133.233
1.00
90.38
ATOM
1784
CB
SER
G
375
96.796
−132.978
134.636
1.00
93.11
ATOM
1785
OG
SER
G
375
96.788
−132.708
133.244
1.00
93.88
ATOM
1786
N
PHE
G
376
95.860
−136.101
135.368
1.00
90.06
ATOM
1787
CA
PHE
G
376
94.920
−137.166
135.037
1.00
93.27
ATOM
1788
C
PHE
G
376
93.895
−137.317
136.156
1.00
95.94
ATOM
1789
O
PHE
G
376
94.034
−136.702
137.212
1.00
95.54
ATOM
1790
CB
PHE
G
376
95.649
−138.495
134.805
1.00
92.86
ATOM
1791
CG
PHE
G
376
96.283
−139.076
136.037
1.00
93.02
ATOM
1792
CD1
PHE
G
376
97.542
−138.660
136.454
1.00
93.40
ATOM
1793
CD2
PHE
G
376
95.628
−140.065
136.766
1.00
92.09
ATOM
1794
CE1
PHE
G
376
98.144
−139.223
137.581
1.00
93.87
ATOM
1795
CE2
PHE
G
376
96.218
−140.634
137.892
1.00
92.28
ATOM
1796
CZ
PHE
G
376
97.479
−140.214
138.300
1.00
94.05
ATOM
1797
N
ASN
G
377
92.870
−138.132
135.930
1.00
99.59
ATOM
1798
CA
ASN
G
377
91.825
−138.327
136.931
1.00
104.81
ATOM
1799
C
ASN
G
377
91.355
−139.774
137.059
1.00
107.26
ATOM
1800
O
ASN
G
377
91.034
−140.429
136.068
1.00
107.33
ATOM
1801
CB
ASN
G
377
90.625
−137.442
136.598
1.00
107.57
ATOM
1802
CG
ASN
G
377
90.145
−137.635
135.176
1.00
110.35
ATOM
1803
OD1
ASN
G
377
90.827
−137.256
134.223
1.00
112.46
ATOM
1804
ND2
ASN
G
377
88.974
−138.242
135.023
1.00
111.65
ATOM
1805
N
CYS
G
378
91.313
−140.259
138.296
1.00
110.71
ATOM
1806
CA
CYS
G
378
90.878
−141.621
138.595
1.00
113.87
ATOM
1807
C
CYS
G
378
90.247
−141.634
139.988
1.00
114.07
ATOM
1808
O
CYS
G
378
90.894
−141.266
140.966
1.00
113.69
ATOM
1809
CB
CYS
G
378
92.069
−142.601
138.540
1.00
116.89
ATOM
1810
SG
CYS
G
378
93.430
−142.309
139.720
1.00
121.15
ATOM
1811
N
GLY
G
379
88.985
−142.047
140.080
1.00
113.75
ATOM
1812
CA
GLY
G
379
88.320
−142.076
141.373
1.00
112.55
ATOM
1813
C
GLY
G
379
87.547
−140.800
141.651
1.00
111.47
ATOM
1814
O
GLY
G
379
86.731
−140.736
142.570
1.00
112.00
ATOM
1815
N
GLY
G
380
87.809
−139.776
140.849
1.00
109.49
ATOM
1816
CA
GLY
G
380
87.123
−138.513
141.024
1.00
107.11
ATOM
1817
C
GLY
G
380
88.074
−137.401
141.410
1.00
105.53
ATOM
1818
O
GLY
G
380
87.672
−136.246
141.521
1.00
106.59
ATOM
1819
N
GLU
G
381
89.342
−137.743
141.611
1.00
102.89
ATOM
1820
CA
GLU
G
381
90.339
−136.749
141.989
1.00
100.20
ATOM
1821
C
GLU
G
381
91.269
−136.414
140.832
1.00
97.39
ATOM
1822
O
GLU
G
381
91.658
−137.291
140.062
1.00
97.65
ATOM
1823
CB
GLU
G
381
91.165
−137.252
143.174
1.00
101.99
ATOM
1824
CG
GLU
G
381
90.341
−137.669
144.376
1.00
104.32
ATOM
1825
CD
GLU
G
381
89.409
−136.574
144.853
1.00
106.86
ATOM
1826
OE1
GLU
G
381
89.884
−135.439
145.071
1.00
108.66
ATOM
1827
OE2
GLU
G
381
88.201
−136.853
145.014
1.00
108.04
ATOM
1828
N
PHE
G
382
91.629
−135.140
140.719
1.00
93.73
ATOM
1829
CA
PHE
G
382
92.513
−134.697
139.648
1.00
89.57
ATOM
1830
C
PHE
G
382
93.963
−134.629
140.104
1.00
88.33
ATOM
1831
O
PHE
G
382
94.338
−133.753
140.882
1.00
88.16
ATOM
1832
CB
PHE
G
382
92.073
−133.326
139.134
1.00
86.63
ATOM
1833
CG
PHE
G
382
90.700
−133.321
138.523
1.00
84.43
ATOM
1834
CD1
PHE
G
382
89.570
−133.512
139.313
1.00
82.70
ATOM
1835
CD2
PHE
G
382
90.536
−133.130
137.155
1.00
83.85
ATOM
1836
CE1
PHE
G
382
88.298
−133.513
138.749
1.00
80.29
ATOM
1837
CE2
PHE
G
382
89.268
−133.130
136.584
1.00
82.03
ATOM
1838
CZ
PHE
G
382
88.149
−133.321
137.383
1.00
80.22
ATOM
1839
N
PHE
G
383
94.777
−135.555
139.607
1.00
87.21
ATOM
1840
CA
PHE
G
383
96.190
−135.607
139.965
1.00
86.08
ATOM
1841
C
PHE
G
383
97.049
−134.663
139.136
1.00
85.60
ATOM
1842
O
PHE
G
383
96.735
−134.368
137.984
1.00
85.11
ATOM
1843
CB
PHE
G
383
96.727
−137.032
139.805
1.00
85.28
ATOM
1844
CG
PHE
G
383
96.120
−138.022
140.755
1.00
85.57
ATOM
1845
CD1
PHE
G
383
94.790
−138.408
140.627
1.00
85.90
ATOM
1846
CD2
PHE
G
383
96.880
−138.571
141.782
1.00
85.81
ATOM
1847
CE1
PHE
G
383
94.226
−139.327
141.508
1.00
85.70
ATOM
1848
CE2
PHE
G
383
96.326
−139.489
142.667
1.00
85.26
ATOM
1849
CZ
PHE
G
383
94.997
−139.868
142.530
1.00
84.70
ATOM
1850
N
TYR
G
384
98.135
−134.190
139.736
1.00
85.21
ATOM
1851
CA
TYR
G
384
99.071
−133.295
139.061
1.00
86.70
ATOM
1852
C
TYR
G
384
100.504
−133.685
139.415
1.00
89.54
ATOM
1853
O
TYR
G
384
101.132
−133.047
140.255
1.00
90.93
ATOM
1854
CB
TYR
G
384
98.812
−131.845
139.473
1.00
85.32
ATOM
1855
CG
TYR
G
384
97.548
−131.256
138.895
1.00
83.12
ATOM
1856
CD1
TYR
G
384
96.321
−131.416
139.533
1.00
82.42
ATOM
1857
CD2
TYR
G
384
97.579
−130.555
137.690
1.00
81.60
ATOM
1858
CE1
TYR
G
384
95.153
−130.891
138.983
1.00
82.41
ATOM
1859
CE2
TYR
G
384
96.422
−130.029
137.132
1.00
81.05
ATOM
1860
CZ
TYR
G
384
95.214
−130.200
137.782
1.00
81.32
ATOM
1861
OH
TYR
G
384
94.070
−129.681
137.223
1.00
78.86
ATOM
1862
N
CYS
G
385
101.010
−134.733
138.764
1.00
93.00
ATOM
1863
CA
CYS
G
385
102.358
−135.249
139.016
1.00
96.10
ATOM
1864
C
CYS
G
385
103.432
−134.478
138.255
1.00
98.98
ATOM
1865
O
CYS
G
385
103.284
−134.196
137.064
1.00
100.31
ATOM
1866
CB
CYS
G
385
102.448
−136.727
138.625
1.00
96.17
ATOM
1867
SG
CYS
G
385
101.237
−137.831
139.415
1.00
97.03
ATOM
1868
N
ASN
G
386
104.522
−134.158
138.944
1.00
101.88
ATOM
1869
CA
ASN
G
386
105.630
−133.416
138.351
1.00
105.68
ATOM
1870
C
ASN
G
386
106.483
−134.318
137.460
1.00
109.06
ATOM
1871
O
ASN
G
386
107.126
−135.249
137.940
1.00
110.00
ATOM
1872
CB
ASN
G
386
106.488
−132.802
139.464
1.00
104.65
ATOM
1873
CG
ASN
G
386
107.278
−131.592
138.997
1.00
104.49
ATOM
1874
OD1
ASN
G
386
107.793
−130.826
139.811
1.00
105.86
ATOM
1875
ND2
ASN
G
386
107.380
−131.417
137.682
1.00
103.57
ATOM
1876
N
SER
G
387
106.489
−134.033
136.161
1.00
112.28
ATOM
1877
CA
SER
G
387
107.255
−134.828
135.204
1.00
115.20
ATOM
1878
C
SER
G
387
108.613
−134.207
134.897
1.00
117.38
ATOM
1879
O
SER
G
387
109.080
−134.244
133.756
1.00
118.83
ATOM
1880
CB
SER
G
387
106.468
−134.982
133.901
1.00
114.78
ATOM
1881
OG
SER
G
387
106.259
−133.722
133.290
1.00
115.93
ATOM
1882
N
ALA
G
388
109.242
−133.635
135.916
1.00
118.94
ATOM
1883
CA
ALA
G
388
110.543
−133.004
135.747
1.00
120.08
ATOM
1884
C
ALA
G
388
111.650
−134.046
135.640
1.00
120.63
ATOM
1885
O
ALA
G
388
112.518
−133.955
134.776
1.00
121.23
ATOM
1886
CB
ALA
G
388
110.821
−132.064
136.915
1.00
120.48
ATOM
1887
N
GLN
G
389
111.612
−135.038
136.523
1.00
121.07
ATOM
1888
CA
GLN
G
389
112.616
−136.094
136.531
1.00
121.87
ATOM
1889
C
GLN
G
389
112.436
−137.082
135.383
1.00
121.47
ATOM
1890
O
GLN
G
389
113.415
−137.619
134.864
1.00
122.53
ATOM
1891
CB
GLN
G
389
112.584
−136.833
137.870
1.00
123.58
ATOM
1892
CG
GLN
G
389
111.184
−137.051
138.405
1.00
127.91
ATOM
1893
CD
GLN
G
389
111.168
−137.823
139.708
1.00
130.19
ATOM
1894
OE1
GLN
G
389
111.948
−137.547
140.620
1.00
132.91
ATOM
1895
NE2
GLN
G
389
110.266
−138.791
139.806
1.00
131.56
ATOM
1896
N
LEU
G
390
111.189
−137.319
134.987
1.00
120.77
ATOM
1897
CA
LEU
G
390
110.899
−138.241
133.892
1.00
119.93
ATOM
1898
C
LEU
G
390
111.556
−137.810
132.589
1.00
119.16
ATOM
1899
O
LEU
G
390
112.076
−138.639
131.843
1.00
119.29
ATOM
1900
CB
LEU
G
390
109.392
−138.349
133.667
1.00
120.27
ATOM
1901
CG
LEU
G
390
108.609
−139.237
134.633
1.00
120.93
ATOM
1902
CD1
LEU
G
390
107.122
−139.075
134.385
1.00
122.76
ATOM
1903
CD2
LEU
G
390
109.028
−140.682
134.437
1.00
121.13
ATOM
1904
N
PHE
G
391
111.525
−136.512
132.312
1.00
117.95
ATOM
1905
CA
PHE
G
391
112.116
−135.993
131.088
1.00
116.69
ATOM
1906
C
PHE
G
391
113.329
−135.117
131.375
1.00
116.29
ATOM
1907
O
PHE
G
391
113.311
−133.915
131.123
1.00
116.61
ATOM
1908
CB
PHE
G
391
111.076
−135.193
130.296
1.00
115.47
ATOM
1909
CG
PHE
G
391
109.902
−136.012
129.830
1.00
113.79
ATOM
1910
CD1
PHE
G
391
108.889
−136.372
130.713
1.00
112.00
ATOM
1911
CD2
PHE
G
391
109.814
−136.430
128.504
1.00
113.65
ATOM
1912
CE1
PHE
G
391
107.806
−137.138
130.284
1.00
111.30
ATOM
1913
CE2
PHE
G
391
108.735
−137.197
128.066
1.00
112.65
ATOM
1914
CZ
PHE
G
391
107.730
−137.550
128.959
1.00
111.37
ATOM
1915
N
ASN
G
392
114.386
−135.730
131.900
1.00
116.37
ATOM
1916
CA
ASN
G
392
115.614
−135.010
132.219
1.00
116.90
ATOM
1917
C
ASN
G
392
116.832
−135.861
131.881
1.00
117.22
ATOM
1918
O
ASN
G
392
117.371
−136.552
132.746
1.00
117.20
ATOM
1919
CB
ASN
G
392
115.653
−134.660
133.710
1.00
117.23
ATOM
1920
CG
ASN
G
392
116.788
−133.711
134.059
1.00
117.04
ATOM
1921
OD1
ASN
G
392
117.373
−133.793
135.141
1.00
116.31
ATOM
1922
ND2
ASN
G
392
117.091
−132.792
133.148
1.00
115.97
ATOM
1923
N
SER
G
393
117.264
−135.811
130.628
1.00
117.25
ATOM
1924
CA
SER
G
393
118.420
−136.587
130.199
1.00
117.84
ATOM
1925
C
SER
G
393
118.898
−136.099
128.838
1.00
118.76
ATOM
1926
O
SER
G
393
118.091
−135.750
127.979
1.00
118.46
ATOM
1927
CB
SER
G
393
118.059
−138.076
130.130
1.00
117.40
ATOM
1928
OG
SER
G
393
116.915
−138.287
129.323
1.00
117.90
ATOM
1929
N
THR
G
394
120.213
−136.069
128.648
1.00
120.79
ATOM
1930
CA
THR
G
394
120.788
−135.615
127.390
1.00
122.12
ATOM
1931
C
THR
G
394
121.239
−136.811
126.565
1.00
123.64
ATOM
1932
O
THR
G
394
121.846
−137.738
127.096
1.00
123.04
ATOM
1933
CB
THR
G
394
122.003
−134.711
127.640
1.00
121.38
ATOM
1934
OG1
THR
G
394
121.701
−133.792
128.694
1.00
121.49
ATOM
1935
CG2
THR
G
394
122.347
−133.924
126.390
1.00
120.33
ATOM
1936
N
TRP
G
395
120.938
−136.791
125.271
1.00
125.53
ATOM
1937
CA
TRP
G
395
121.324
−137.885
124.389
1.00
127.71
ATOM
1938
C
TRP
G
395
122.040
−137.385
123.138
1.00
130.76
ATOM
1939
O
TRP
G
395
121.444
−136.713
122.296
1.00
130.73
ATOM
1940
CB
TRP
G
395
120.092
−138.696
123.976
1.00
124.98
ATOM
1941
CG
TRP
G
395
119.330
−139.263
125.127
1.00
122.80
ATOM
1942
CD1
TRP
G
395
118.578
−138.573
126.032
1.00
122.44
ATOM
1943
CD2
TRP
G
395
119.259
−140.641
125.511
1.00
121.88
ATOM
1944
NE1
TRP
G
395
118.041
−139.435
126.957
1.00
122.03
ATOM
1945
CE2
TRP
G
395
118.442
−140.710
126.662
1.00
121.61
ATOM
1946
CE3
TRP
G
395
119.804
−141.823
124.995
1.00
122.03
ATOM
1947
CZ2
TRP
G
395
118.159
−141.918
127.308
1.00
121.03
ATOM
1948
CZ3
TRP
G
395
119.521
−143.024
125.638
1.00
121.12
ATOM
1949
CH2
TRP
G
395
118.705
−143.061
126.782
1.00
120.35
ATOM
1950
N
ASN
G
396
123.322
−137.722
123.023
1.00
134.68
ATOM
1951
CA
ASN
G
396
124.132
−137.319
121.877
1.00
138.49
ATOM
1952
C
ASN
G
396
125.278
−138.306
121.699
1.00
140.34
ATOM
1953
O
ASN
G
396
126.028
−138.237
120.723
1.00
140.16
ATOM
1954
CB
ASN
G
396
124.702
−135.914
122.091
1.00
139.54
ATOM
1955
CG
ASN
G
396
125.710
−135.858
123.225
1.00
140.48
ATOM
1956
OD1
ASN
G
396
125.396
−136.194
124.367
1.00
140.41
ATOM
1957
ND2
ASN
G
396
126.929
−135.431
122.914
1.00
139.91
ATOM
1958
N
ASN
G
397
125.405
−139.223
122.653
1.00
142.71
ATOM
1959
CA
ASN
G
397
126.461
−140.225
122.616
1.00
145.52
ATOM
1960
C
ASN
G
397
126.235
−141.263
123.712
1.00
147.30
ATOM
1961
O
ASN
G
397
126.975
−141.314
124.696
1.00
147.83
ATOM
1962
CB
ASN
G
397
127.820
−139.546
122.804
1.00
145.45
ATOM
1963
CG
ASN
G
397
128.980
−140.452
122.449
1.00
146.09
ATOM
1964
OD1
ASN
G
397
130.135
−140.031
122.478
1.00
147.69
ATOM
1965
ND2
ASN
G
397
128.680
−141.700
122.109
1.00
146.44
ATOM
1966
N
ASN
G
401
125.206
−142.087
123.536
1.00
148.95
ATOM
1967
CA
ASN
G
401
124.874
−143.125
124.505
1.00
150.19
ATOM
1968
C
ASN
G
401
124.087
−144.258
123.850
1.00
151.32
ATOM
1969
O
ASN
G
401
122.864
−144.187
123.729
1.00
151.15
ATOM
1970
CB
ASN
G
401
124.057
−142.526
125.654
1.00
149.72
ATOM
1971
CG
ASN
G
401
123.716
−143.547
126.723
1.00
150.07
ATOM
1972
OD1
ASN
G
401
123.043
−144.543
126.455
1.00
150.13
ATOM
1973
ND2
ASN
G
401
124.180
−143.304
127.943
1.00
150.04
ATOM
1974
N
THR
G
402
124.798
−145.301
123.431
1.00
152.32
ATOM
1975
CA
THR
G
402
124.171
−146.452
122.790
1.00
152.72
ATOM
1976
C
THR
G
402
124.884
−147.746
123.178
1.00
152.78
ATOM
1977
O
THR
G
402
125.762
−148.222
122.457
1.00
152.62
ATOM
1978
CB
THR
G
402
124.193
−146.315
121.249
1.00
152.55
ATOM
1979
OG1
THR
G
402
123.528
−145.105
120.864
1.00
152.61
ATOM
1980
CG2
THR
G
402
123.489
−147.498
120.597
1.00
152.80
ATOM
1981
N
GLU
G
403
124.503
−148.307
124.322
1.00
153.02
ATOM
1982
CA
GLU
G
403
125.102
−149.547
124.806
1.00
153.40
ATOM
1983
C
GLU
G
403
124.013
−150.508
125.281
1.00
153.32
ATOM
1984
O
GLU
G
403
123.311
−151.112
124.468
1.00
152.98
ATOM
1985
CB
GLU
G
403
126.074
−149.251
125.952
1.00
153.38
ATOM
1986
CG
GLU
G
403
126.971
−150.422
126.323
1.00
154.46
ATOM
1987
CD
GLU
G
403
127.851
−150.127
127.522
1.00
155.23
ATOM
1988
OE1
GLU
G
403
128.568
−149.104
127.499
1.00
155.71
ATOM
1989
OE2
GLU
G
403
127.828
−150.921
128.486
1.00
155.97
ATOM
1990
N
GLY
G
404
123.875
−150.647
126.597
1.00
153.51
ATOM
1991
CA
GLY
G
404
122.862
−151.531
127.148
1.00
153.40
ATOM
1992
C
GLY
G
404
123.409
−152.822
127.728
1.00
153.73
ATOM
1993
O
GLY
G
404
123.831
−153.715
126.991
1.00
153.69
ATOM
1994
N
SER
G
405
123.400
−152.922
129.054
1.00
153.35
ATOM
1995
CA
SER
G
405
123.888
−154.112
129.745
1.00
152.70
ATOM
1996
C
SER
G
405
123.183
−154.291
131.086
1.00
152.14
ATOM
1997
O
SER
G
405
122.394
−155.221
131.259
1.00
151.89
ATOM
1998
CB
SER
G
405
125.401
−154.021
129.962
1.00
152.88
ATOM
1999
OG
SER
G
405
126.096
−154.051
128.728
1.00
152.70
ATOM
2000
N
ASN
G
406
123.473
−153.398
132.031
1.00
151.38
ATOM
2001
CA
ASN
G
406
122.864
−153.445
133.359
1.00
150.36
ATOM
2002
C
ASN
G
406
123.489
−152.410
134.294
1.00
149.65
ATOM
2003
O
ASN
G
406
124.666
−152.503
134.641
1.00
149.18
ATOM
2004
CB
ASN
G
406
123.020
−154.842
133.970
1.00
150.31
ATOM
2005
CG
ASN
G
406
122.212
−155.018
135.243
1.00
150.00
ATOM
2006
OD1
ASN
G
406
122.418
−154.308
136.227
1.00
150.04
ATOM
2007
ND2
ASN
G
406
121.284
−155.970
135.228
1.00
148.55
ATOM
2008
N
ASN
G
407
122.691
−151.425
134.696
1.00
149.20
ATOM
2009
CA
ASN
G
407
123.153
−150.371
135.596
1.00
148.98
ATOM
2010
C
ASN
G
407
122.039
−149.959
136.557
1.00
148.75
ATOM
2011
O
ASN
G
407
120.905
−149.720
136.141
1.00
148.64
ATOM
2012
CB
ASN
G
407
123.622
−149.154
134.792
1.00
148.85
ATOM
2013
CG
ASN
G
407
124.837
−149.454
133.934
1.00
148.15
ATOM
2014
OD1
ASN
G
407
125.883
−149.861
134.440
1.00
147.21
ATOM
2015
ND2
ASN
G
407
124.704
−149.252
132.627
1.00
146.76
ATOM
2016
N
THR
G
408
122.372
−149.876
137.843
1.00
148.42
ATOM
2017
CA
THR
G
408
121.400
−149.505
138.866
1.00
147.81
ATOM
2018
C
THR
G
408
121.620
−148.095
139.413
1.00
147.62
ATOM
2019
O
THR
G
408
122.740
−147.710
139.750
1.00
147.36
ATOM
2020
CB
THR
G
408
121.433
−150.503
140.047
1.00
147.47
ATOM
2021
OG1
THR
G
408
121.128
−151.820
139.570
1.00
146.97
ATOM
2022
CG2
THR
G
408
120.415
−150.110
141.110
1.00
147.04
ATOM
2023
N
GLU
G
409
120.532
−147.333
139.497
1.00
147.14
ATOM
2024
CA
GLU
G
409
120.563
−145.965
140.005
1.00
146.36
ATOM
2025
C
GLU
G
409
119.161
−145.527
140.417
1.00
145.32
ATOM
2026
O
GLU
G
409
118.354
−145.122
139.579
1.00
145.40
ATOM
2027
CB
GLU
G
409
121.116
−145.012
138.938
1.00
146.73
ATOM
2028
CG
GLU
G
409
120.856
−143.531
139.211
1.00
147.62
ATOM
2029
CD
GLU
G
409
121.396
−143.060
140.552
1.00
148.32
ATOM
2030
OE1
GLU
G
409
121.186
−141.875
140.891
1.00
147.74
ATOM
2031
OE2
GLU
G
409
122.029
−143.866
141.267
1.00
149.23
ATOM
2032
N
GLY
G
410
118.878
−145.613
141.713
1.00
143.74
ATOM
2033
CA
GLY
G
410
117.570
−145.228
142.210
1.00
141.66
ATOM
2034
C
GLY
G
410
116.524
−146.283
141.903
1.00
140.56
ATOM
2035
O
GLY
G
410
115.851
−146.210
140.874
1.00
140.48
ATOM
2036
N
ASN
G
412
116.401
−147.261
142.799
1.00
138.86
ATOM
2037
CA
ASN
G
412
115.446
−148.363
142.670
1.00
136.44
ATOM
2038
C
ASN
G
412
114.351
−148.049
141.651
1.00
134.58
ATOM
2039
O
ASN
G
412
114.474
−148.377
140.470
1.00
133.27
ATOM
2040
CB
ASN
G
412
114.818
−148.658
144.038
1.00
137.07
ATOM
2041
CG
ASN
G
412
114.127
−150.009
144.090
1.00
138.01
ATOM
2042
OD1
ASN
G
412
113.251
−150.306
143.279
1.00
138.79
ATOM
2043
ND2
ASN
G
412
114.519
−150.835
145.055
1.00
137.47
ATOM
2044
N
THR
G
413
113.283
−147.412
142.121
1.00
132.39
ATOM
2045
CA
THR
G
413
112.167
−147.028
141.264
1.00
129.59
ATOM
2046
C
THR
G
413
111.876
−145.553
141.502
1.00
127.51
ATOM
2047
O
THR
G
413
111.733
−145.116
142.645
1.00
127.21
ATOM
2048
CB
THR
G
413
110.899
−147.848
141.575
1.00
129.45
ATOM
2049
OG1
THR
G
413
110.560
−147.703
142.959
1.00
130.30
ATOM
2050
CG2
THR
G
413
111.125
−149.319
141.259
1.00
129.33
ATOM
2051
N
ILE
G
414
111.792
−144.788
140.418
1.00
125.10
ATOM
2052
CA
ILE
G
414
111.543
−143.356
140.515
1.00
122.12
ATOM
2053
C
ILE
G
414
110.120
−143.022
140.958
1.00
119.27
ATOM
2054
O
ILE
G
414
109.151
−143.618
140.489
1.00
118.60
ATOM
2055
CB
ILE
G
414
111.838
−142.653
139.169
1.00
121.95
ATOM
2056
CG1
ILE
G
414
111.801
−141.138
139.358
1.00
122.52
ATOM
2057
CG2
ILE
G
414
110.830
−143.086
138.118
1.00
121.32
ATOM
2058
CD1
ILE
G
414
112.797
−140.620
140.384
1.00
122.64
ATOM
2059
N
THR
G
415
110.003
−142.060
141.866
1.00
115.70
ATOM
2060
CA
THR
G
415
108.704
−141.642
142.387
1.00
111.52
ATOM
2061
C
THR
G
415
108.362
−140.206
141.981
1.00
109.61
ATOM
2062
O
THR
G
415
109.175
−139.293
142.141
1.00
109.81
ATOM
2063
CB
THR
G
415
108.676
−141.739
143.923
1.00
110.78
ATOM
2064
OG1
THR
G
415
109.874
−141.165
144.460
1.00
110.36
ATOM
2065
CG2
THR
G
415
108.569
−143.179
144.369
1.00
109.69
ATOM
2066
N
LEU
G
416
107.150
−140.018
141.463
1.00
106.18
ATOM
2067
CA
LEU
G
416
106.684
−138.706
141.012
1.00
103.07
ATOM
2068
C
LEU
G
416
105.914
−137.919
142.070
1.00
101.81
ATOM
2069
O
LEU
G
416
104.998
−138.443
142.708
1.00
101.50
ATOM
2070
CB
LEU
G
416
105.775
−138.847
139.791
1.00
101.73
ATOM
2071
CG
LEU
G
416
106.344
−139.279
138.433
1.00
101.54
ATOM
2072
CD1
LEU
G
416
107.506
−138.367
138.062
1.00
100.93
ATOM
2073
CD2
LEU
G
416
106.797
−140.724
138.497
1.00
102.75
ATOM
2074
N
PRO
G
417
106.269
−136.638
142.261
1.00
100.49
ATOM
2075
CA
PRO
G
417
105.601
−135.778
143.242
1.00
99.11
ATOM
2076
C
PRO
G
417
104.244
−135.385
142.674
1.00
97.27
ATOM
2077
O
PRO
G
417
104.181
−134.634
141.706
1.00
96.57
ATOM
2078
CB
PRO
G
417
106.539
−134.573
143.338
1.00
99.33
ATOM
2079
CG
PRO
G
417
107.875
−135.120
142.895
1.00
100.96
ATOM
2080
CD
PRO
G
417
107.462
−135.964
141.726
1.00
101.14
ATOM
2081
N
CYS
G
418
103.158
−135.878
143.255
1.00
96.07
ATOM
2082
CA
CYS
G
418
101.840
−135.543
142.722
1.00
95.36
ATOM
2083
C
CYS
G
418
100.974
−134.814
143.737
1.00
94.31
ATOM
2084
O
CYS
G
418
101.186
−134.933
144.941
1.00
93.95
ATOM
2085
CB
CYS
G
418
101.124
−136.816
142.273
1.00
96.19
ATOM
2086
SG
CYS
G
418
100.205
−136.655
140.711
1.00
99.96
ATOM
2087
N
ARG
G
419
99.992
−134.065
143.243
1.00
93.30
ATOM
2088
CA
ARG
G
419
99.085
−133.325
144.112
1.00
92.31
ATOM
2089
C
ARG
G
419
97.658
−133.284
143.571
1.00
90.72
ATOM
2090
O
ARG
G
419
97.433
−132.982
142.396
1.00
90.53
ATOM
2091
CB
ARG
G
419
99.596
−131.890
144.314
1.00
93.73
ATOM
2092
CG
ARG
G
419
98.698
−131.006
145.181
1.00
95.93
ATOM
2093
CD
ARG
G
419
99.220
−129.571
145.236
1.00
99.25
ATOM
2094
NE
ARG
G
419
98.204
−128.611
145.670
1.00
100.53
ATOM
2095
CZ
ARG
G
419
97.837
−128.412
146.933
1.00
100.92
ATOM
2096
NH1
ARG
G
419
98.402
−129.102
147.916
1.00
100.24
ATOM
2097
NH2
ARG
G
419
96.900
−127.517
147.214
1.00
100.94
ATOM
2098
N
ILE
G
420
96.699
−133.601
144.436
1.00
88.67
ATOM
2099
CA
ILE
G
420
95.283
−133.579
144.078
1.00
86.76
ATOM
2100
C
ILE
G
420
94.765
−132.157
144.276
1.00
86.13
ATOM
2101
O
ILE
G
420
95.033
−131.530
145.302
1.00
86.62
ATOM
2102
CB
ILE
G
420
94.463
−134.540
144.969
1.00
85.30
ATOM
2103
CG1
ILE
G
420
94.795
−135.997
144.627
1.00
84.63
ATOM
2104
CG2
ILE
G
420
92.977
−134.295
144.768
1.00
85.53
ATOM
2105
CD1
ILE
G
420
96.188
−136.429
145.018
1.00
84.54
ATOM
2106
N
LYS
G
421
94.021
−131.645
143.302
1.00
84.49
ATOM
2107
CA
LYS
G
421
93.523
−130.279
143.400
1.00
83.10
ATOM
2108
C
LYS
G
421
92.006
−130.151
143.259
1.00
83.34
ATOM
2109
O
LYS
G
421
91.341
−131.023
142.702
1.00
83.53
ATOM
2110
CB
LYS
G
421
94.224
−129.405
142.343
1.00
82.25
ATOM
2111
CG
LYS
G
421
95.756
−129.478
142.395
1.00
82.29
ATOM
2112
CD
LYS
G
421
96.428
−128.598
141.347
1.00
81.95
ATOM
2113
CE
LYS
G
421
97.882
−128.375
141.743
1.00
84.09
ATOM
2114
NZ
LYS
G
421
98.489
−127.187
141.078
1.00
83.94
ATOM
2115
N
GLN
G
422
91.471
−129.045
143.768
1.00
83.63
ATOM
2116
CA
GLN
G
422
90.040
−128.764
143.702
1.00
82.61
ATOM
2117
C
GLN
G
422
89.728
−127.802
142.565
1.00
80.65
ATOM
2118
O
GLN
G
422
88.823
−128.044
141.770
1.00
78.92
ATOM
2119
CB
GLN
G
422
89.553
−128.181
145.033
1.00
84.13
ATOM
2120
CG
GLN
G
422
89.286
−129.228
146.109
1.00
88.24
ATOM
2121
CD
GLN
G
422
88.821
−128.620
147.421
1.00
91.10
ATOM
2122
OE1
GLN
G
422
89.614
−128.054
148.174
1.00
92.63
ATOM
2123
NE2
GLN
G
422
87.527
−128.731
147.699
1.00
91.83
ATOM
2124
N
ILE
G
423
90.474
−126.706
142.493
1.00
79.69
ATOM
2125
CA
ILE
G
423
90.276
−125.734
141.431
1.00
79.70
ATOM
2126
C
ILE
G
423
91.021
−126.251
140.208
1.00
79.36
ATOM
2127
O
ILE
G
423
92.238
−126.436
140.240
1.00
81.30
ATOM
2128
CB
ILE
G
423
90.807
−124.356
141.858
1.00
79.75
ATOM
2129
CG1
ILE
G
423
89.917
−123.811
142.982
1.00
80.64
ATOM
2130
CG2
ILE
G
423
90.841
−123.411
140.668
1.00
79.15
ATOM
2131
CD1
ILE
G
423
90.446
−122.563
143.643
1.00
83.89
ATOM
2132
N
ILE
G
424
90.275
−126.493
139.138
1.00
78.23
ATOM
2133
CA
ILE
G
424
90.833
−127.038
137.915
1.00
77.77
ATOM
2134
C
ILE
G
424
90.580
−126.185
136.690
1.00
77.60
ATOM
2135
O
ILE
G
424
89.543
−125.539
136.576
1.00
78.36
ATOM
2136
CB
ILE
G
424
90.208
−128.401
137.631
1.00
78.68
ATOM
2137
CG1
ILE
G
424
90.294
−129.256
138.885
1.00
80.96
ATOM
2138
CG2
ILE
G
424
90.893
−129.069
136.451
1.00
80.04
ATOM
2139
CD1
ILE
G
424
89.310
−130.360
138.897
1.00
85.27
ATOM
2140
N
ASN
G
425
91.533
−126.182
135.766
1.00
78.21
ATOM
2141
CA
ASN
G
425
91.356
−125.444
134.521
1.00
79.38
ATOM
2142
C
ASN
G
425
90.717
−126.445
133.562
1.00
81.00
ATOM
2143
O
ASN
G
425
91.281
−127.506
133.291
1.00
82.92
ATOM
2144
CB
ASN
G
425
92.697
−124.946
133.978
1.00
78.48
ATOM
2145
CG
ASN
G
425
93.007
−123.526
134.408
1.00
79.22
ATOM
2146
OD1
ASN
G
425
92.243
−122.601
134.123
1.00
78.79
ATOM
2147
ND2
ASN
G
425
94.136
−123.341
135.080
1.00
80.19
ATOM
2148
N
MET
G
426
89.534
−126.112
133.057
1.00
82.44
ATOM
2149
CA
MET
G
426
88.803
−127.010
132.169
1.00
83.15
ATOM
2150
C
MET
G
426
89.441
−127.260
130.810
1.00
82.81
ATOM
2151
O
MET
G
426
89.996
−126.349
130.194
1.00
81.41
ATOM
2152
CB
MET
G
426
87.378
−126.496
131.982
1.00
84.29
ATOM
2153
CG
MET
G
426
86.668
−126.263
133.303
1.00
83.67
ATOM
2154
SD
MET
G
426
84.893
−126.182
133.114
1.00
83.84
ATOM
2155
CE
MET
G
426
84.500
−127.928
133.137
1.00
84.40
ATOM
2156
N
TRP
G
427
89.355
−128.509
130.353
1.00
82.00
ATOM
2157
CA
TRP
G
427
89.909
−128.910
129.063
1.00
81.18
ATOM
2158
C
TRP
G
427
88.857
−128.872
127.963
1.00
80.45
ATOM
2159
O
TRP
G
427
89.182
−128.678
126.793
1.00
80.26
ATOM
2160
CB
TRP
G
427
90.501
−130.323
129.142
1.00
81.81
ATOM
2161
CG
TRP
G
427
89.522
−131.397
129.531
1.00
82.28
ATOM
2162
CD1
TRP
G
427
89.242
−131.834
130.794
1.00
82.98
ATOM
2163
CD2
TRP
G
427
88.708
−132.181
128.646
1.00
81.40
ATOM
2164
NE1
TRP
G
427
88.310
−132.843
130.751
1.00
82.68
ATOM
2165
CE2
TRP
G
427
87.964
−133.076
129.447
1.00
81.58
ATOM
2166
CE3
TRP
G
427
88.536
−132.213
127.256
1.00
80.71
ATOM
2167
CZ2
TRP
G
427
87.061
−133.996
128.902
1.00
81.39
ATOM
2168
CZ3
TRP
G
427
87.637
−133.130
126.715
1.00
80.74
ATOM
2169
CH2
TRP
G
427
86.912
−134.007
127.539
1.00
80.83
ATOM
2170
N
GLN
G
428
87.596
−129.059
128.341
1.00
80.48
ATOM
2171
CA
GLN
G
428
86.509
−129.047
127.370
1.00
80.94
ATOM
2172
C
GLN
G
428
86.367
−127.664
126.752
1.00
80.28
ATOM
2173
O
GLN
G
428
86.432
−127.507
125.534
1.00
80.34
ATOM
2174
CB
GLN
G
428
85.192
−129.450
128.033
1.00
82.24
ATOM
2175
CG
GLN
G
428
85.271
−130.727
128.850
1.00
84.02
ATOM
2176
CD
GLN
G
428
85.490
−130.459
130.327
1.00
85.70
ATOM
2177
OE1
GLN
G
428
86.450
−129.794
130.718
1.00
86.37
ATOM
2178
NE2
GLN
G
428
84.593
−130.976
131.157
1.00
88.20
ATOM
2179
N
GLU
G
429
86.168
−126.661
127.599
1.00
79.28
ATOM
2180
CA
GLU
G
429
86.028
−125.290
127.128
1.00
79.36
ATOM
2181
C
GLU
G
429
86.891
−124.365
127.975
1.00
77.22
ATOM
2182
O
GLU
G
429
87.281
−124.718
129.088
1.00
77.49
ATOM
2183
CB
GLU
G
429
84.558
−124.850
127.196
1.00
82.15
ATOM
2184
CG
GLU
G
429
84.005
−124.666
128.603
1.00
82.38
ATOM
2185
CD
GLU
G
429
82.538
−124.263
128.606
1.00
83.05
ATOM
2186
OE1
GLU
G
429
82.199
−123.225
127.998
1.00
81.83
ATOM
2187
OE2
GLU
G
429
81.723
−124.988
129.215
1.00
83.79
ATOM
2188
N
VAL
G
430
87.199
−123.187
127.449
1.00
74.05
ATOM
2189
CA
VAL
G
430
88.009
−122.237
128.193
1.00
72.33
ATOM
2190
C
VAL
G
430
87.291
−121.876
129.491
1.00
72.05
ATOM
2191
O
VAL
G
430
86.126
−121.489
129.473
1.00
73.40
ATOM
2192
CB
VAL
G
430
88.240
−120.955
127.377
1.00
72.15
ATOM
2193
CG1
VAL
G
430
89.157
−120.012
128.135
1.00
70.59
ATOM
2194
CG2
VAL
G
430
88.826
−121.304
126.022
1.00
72.50
ATOM
2195
N
GLY
G
431
87.983
−122.013
130.616
1.00
71.44
ATOM
2196
CA
GLY
G
431
87.367
−121.693
131.891
1.00
70.65
ATOM
2197
C
GLY
G
431
87.947
−122.483
133.046
1.00
69.99
ATOM
2198
O
GLY
G
431
88.954
−123.168
132.884
1.00
72.09
ATOM
2199
N
LYS
G
432
87.319
−122.386
134.214
1.00
68.32
ATOM
2200
CA
LYS
G
432
87.785
−123.103
135.397
1.00
66.54
ATOM
2201
C
LYS
G
432
86.663
−123.912
136.026
1.00
64.43
ATOM
2202
O
LYS
G
432
85.510
−123.822
135.611
1.00
66.65
ATOM
2203
CB
LYS
G
432
88.344
−122.123
136.434
1.00
68.76
ATOM
2204
CG
LYS
G
432
89.580
−121.362
135.973
1.00
71.24
ATOM
2205
CD
LYS
G
432
90.008
−120.336
137.012
1.00
72.43
ATOM
2206
CE
LYS
G
432
91.167
−119.486
136.515
1.00
74.60
ATOM
2207
NZ
LYS
G
432
92.391
−120.287
136.230
1.00
76.20
ATOM
2208
N
ALA
G
433
87.008
−124.700
137.036
1.00
61.60
ATOM
2209
CA
ALA
G
433
86.031
−125.529
137.721
1.00
60.62
ATOM
2210
C
ALA
G
433
86.467
−125.778
139.156
1.00
61.66
ATOM
2211
O
ALA
G
433
87.655
−125.757
139.464
1.00
65.08
ATOM
2212
CB
ALA
G
433
85.872
−126.850
136.989
1.00
59.62
ATOM
2213
N
MET
G
434
85.495
−126.019
140.027
1.00
61.86
ATOM
2214
CA
MET
G
434
85.756
−126.272
141.439
1.00
62.17
ATOM
2215
C
MET
G
434
85.099
−127.572
141.885
1.00
63.75
ATOM
2216
O
MET
G
434
83.884
−127.727
141.762
1.00
65.83
ATOM
2217
CB
MET
G
434
85.203
−125.123
142.283
1.00
61.94
ATOM
2218
CG
MET
G
434
84.957
−125.495
143.737
1.00
62.90
ATOM
2219
SD
MET
G
434
86.262
−125.005
144.862
1.00
64.78
ATOM
2220
CE
MET
G
434
85.342
−123.924
145.974
1.00
64.90
ATOM
2221
N
TYR
G
435
85.890
−128.501
142.413
1.00
63.38
ATOM
2222
CA
TYR
G
435
85.343
−129.777
142.874
1.00
61.59
ATOM
2223
C
TYR
G
435
85.401
−129.929
144.388
1.00
62.48
ATOM
2224
O
TYR
G
435
86.030
−129.129
145.079
1.00
62.27
ATOM
2225
CB
TYR
G
435
86.079
−130.945
142.219
1.00
58.59
ATOM
2226
CG
TYR
G
435
85.750
−131.133
140.759
1.00
54.66
ATOM
2227
CD1
TYR
G
435
86.207
−130.237
139.798
1.00
52.26
ATOM
2228
CD2
TYR
G
435
84.967
−132.206
140.340
1.00
57.11
ATOM
2229
CE1
TYR
G
435
85.893
−130.406
138.453
1.00
54.48
ATOM
2230
CE2
TYR
G
435
84.646
−132.384
138.999
1.00
57.17
ATOM
2231
CZ
TYR
G
435
85.110
−131.482
138.062
1.00
55.72
ATOM
2232
OH
TYR
G
435
84.781
−131.663
136.738
1.00
55.13
ATOM
2233
N
ALA
G
436
84.747
−130.967
144.897
1.00
64.73
ATOM
2234
CA
ALA
G
436
84.713
−131.229
146.331
1.00
69.52
ATOM
2235
C
ALA
G
436
86.048
−131.755
146.862
1.00
73.34
ATOM
2236
O
ALA
G
436
86.882
−132.251
146.104
1.00
74.12
ATOM
2237
CB
ALA
G
436
83.598
−132.225
146.645
1.00
68.49
ATOM
2238
N
PRO
G
437
86.266
−131.648
148.184
1.00
77.56
ATOM
2239
CA
PRO
G
437
87.501
−132.114
148.818
1.00
80.89
ATOM
2240
C
PRO
G
437
87.721
−133.611
148.599
1.00
85.07
ATOM
2241
O
PRO
G
437
86.766
−134.365
148.413
1.00
86.90
ATOM
2242
CB
PRO
G
437
87.285
−131.754
150.285
1.00
79.74
ATOM
2243
CG
PRO
G
437
86.421
−130.527
150.197
1.00
78.93
ATOM
2244
CD
PRO
G
437
85.409
−130.972
149.171
1.00
77.85
ATOM
2245
N
PRO
G
438
88.988
−134.058
148.617
1.00
88.61
ATOM
2246
CA
PRO
G
438
89.362
−135.460
148.416
1.00
91.38
ATOM
2247
C
PRO
G
438
88.540
−136.458
149.225
1.00
95.06
ATOM
2248
O
PRO
G
438
88.062
−136.149
150.318
1.00
94.95
ATOM
2249
CB
PRO
G
438
90.840
−135.467
148.790
1.00
89.15
ATOM
2250
CG
PRO
G
438
91.284
−134.125
148.301
1.00
87.77
ATOM
2251
CD
PRO
G
438
90.189
−133.240
148.859
1.00
88.31
ATOM
2252
N
ILE
G
439
88.379
−137.655
148.672
1.00
99.51
ATOM
2253
CA
ILE
G
439
87.615
−138.713
149.320
1.00
105.19
ATOM
2254
C
ILE
G
439
88.361
−139.228
150.546
1.00
110.13
ATOM
2255
O
ILE
G
439
89.590
−139.212
150.581
1.00
110.70
ATOM
2256
CB
ILE
G
439
87.395
−139.884
148.354
1.00
104.20
ATOM
2257
CG1
ILE
G
439
87.009
−139.347
146.973
1.00
103.55
ATOM
2258
CG2
ILE
G
439
86.297
−140.795
148.882
1.00
104.68
ATOM
2259
CD1
ILE
G
439
87.025
−140.395
145.894
1.00
105.15
ATOM
2260
N
ARG
G
440
87.613
−139.688
151.544
1.00
116.12
ATOM
2261
CA
ARG
G
440
88.200
−140.192
152.779
1.00
122.02
ATOM
2262
C
ARG
G
440
89.016
−141.478
152.623
1.00
124.42
ATOM
2263
O
ARG
G
440
90.028
−141.660
153.300
1.00
125.60
ATOM
2264
CB
ARG
G
440
87.096
−140.376
153.833
1.00
124.40
ATOM
2265
CG
ARG
G
440
85.821
−141.037
153.316
1.00
128.47
ATOM
2266
CD
ARG
G
440
85.962
−142.547
153.275
1.00
132.51
ATOM
2267
NE
ARG
G
440
85.509
−143.111
152.007
1.00
135.84
ATOM
2268
CZ
ARG
G
440
85.710
−144.374
151.643
1.00
137.31
ATOM
2269
NH1
ARG
G
440
86.354
−145.200
152.456
1.00
137.16
ATOM
2270
NH2
ARG
G
440
85.275
−144.810
150.467
1.00
136.49
ATOM
2271
N
GLY
G
441
88.592
−142.358
151.721
1.00
125.98
ATOM
2272
CA
GLY
G
441
89.305
−143.609
151.521
1.00
127.56
ATOM
2273
C
GLY
G
441
90.602
−143.502
150.739
1.00
128.74
ATOM
2274
O
GLY
G
441
91.025
−142.412
150.347
1.00
128.11
ATOM
2275
N
GLN
G
442
91.230
−144.653
150.518
1.00
129.91
ATOM
2276
CA
GLN
G
442
92.483
−144.745
149.780
1.00
130.78
ATOM
2277
C
GLN
G
442
92.234
−144.787
148.275
1.00
131.13
ATOM
2278
O
GLN
G
442
91.299
−145.438
147.805
1.00
130.50
ATOM
2279
CB
GLN
G
442
93.251
−145.997
150.219
1.00
132.26
ATOM
2280
CG
GLN
G
442
93.839
−146.801
149.072
1.00
134.25
ATOM
2281
CD
GLN
G
442
95.123
−147.506
149.454
1.00
135.13
ATOM
2282
OE1
GLN
G
442
95.125
−148.447
150.248
1.00
136.02
ATOM
2283
NE2
GLN
G
442
96.233
−147.040
148.897
1.00
134.96
ATOM
2284
N
ILE
G
443
93.084
−144.096
147.524
1.00
131.67
ATOM
2285
CA
ILE
G
443
92.961
−144.041
146.073
1.00
132.30
ATOM
2286
C
ILE
G
443
94.142
−144.725
145.398
1.00
131.73
ATOM
2287
O
ILE
G
443
95.271
−144.238
145.452
1.00
131.38
ATOM
2288
CB
ILE
G
443
92.890
−142.582
145.591
1.00
133.10
ATOM
2289
CG1
ILE
G
443
91.729
−141.871
146.291
1.00
133.63
ATOM
2290
CG2
ILE
G
443
92.701
−142.535
144.080
1.00
134.13
ATOM
2291
CD1
ILE
G
443
91.703
−140.384
146.055
1.00
133.79
ATOM
2292
N
ARG
G
444
93.874
−145.856
144.759
1.00
131.74
ATOM
2293
CA
ARG
G
444
94.909
−146.629
144.078
1.00
131.48
ATOM
2294
C
ARG
G
444
94.593
−146.714
142.583
1.00
129.69
ATOM
2295
O
ARG
G
444
93.492
−147.113
142.205
1.00
129.68
ATOM
2296
CB
ARG
G
444
94.964
−148.037
144.693
1.00
133.90
ATOM
2297
CG
ARG
G
444
96.261
−148.390
145.433
1.00
136.43
ATOM
2298
CD
ARG
G
444
96.037
−149.515
146.449
1.00
138.19
ATOM
2299
NE
ARG
G
444
97.247
−150.283
146.748
1.00
139.51
ATOM
2300
CZ
ARG
G
444
98.290
−149.830
147.441
1.00
140.29
ATOM
2301
NH1
ARG
G
444
98.294
−148.595
147.929
1.00
140.09
ATOM
2302
NH2
ARG
G
444
99.338
−150.619
147.647
1.00
140.64
ATOM
2303
N
CYS
G
445
95.543
−146.334
141.732
1.00
127.32
ATOM
2304
CA
CYS
G
445
95.316
−146.391
140.286
1.00
124.83
ATOM
2305
C
CYS
G
445
96.544
−146.962
139.558
1.00
123.33
ATOM
2306
O
CYS
G
445
97.684
−146.679
139.926
1.00
123.02
ATOM
2307
CB
CYS
G
445
94.974
−144.987
139.740
1.00
124.31
ATOM
2308
SG
CYS
G
445
93.684
−144.087
140.680
1.00
124.41
ATOM
2309
N
SER
G
446
96.299
−147.780
138.536
1.00
121.97
ATOM
2310
CA
SER
G
446
97.366
−148.402
137.752
1.00
119.88
ATOM
2311
C
SER
G
446
97.031
−148.373
136.262
1.00
117.92
ATOM
2312
O
SER
G
446
95.924
−148.733
135.859
1.00
117.72
ATOM
2313
CB
SER
G
446
97.574
−149.853
138.202
1.00
120.03
ATOM
2314
OG
SER
G
446
96.407
−150.627
137.986
1.00
120.27
ATOM
2315
N
SER
G
447
97.994
−147.955
135.448
1.00
114.74
ATOM
2316
CA
SER
G
447
97.790
−147.875
134.008
1.00
112.04
ATOM
2317
C
SER
G
447
99.096
−148.079
133.241
1.00
108.70
ATOM
2318
O
SER
G
447
100.182
−147.987
133.812
1.00
108.62
ATOM
2319
CB
SER
G
447
97.173
−146.518
133.655
1.00
113.67
ATOM
2320
OG
SER
G
447
97.856
−145.468
134.314
1.00
114.63
ATOM
2321
N
ASN
G
448
98.975
−148.359
131.946
1.00
104.80
ATOM
2322
CA
ASN
G
448
100.127
−148.587
131.084
1.00
101.05
ATOM
2323
C
ASN
G
448
100.392
−147.407
130.161
1.00
98.08
ATOM
2324
O
ASN
G
448
99.549
−147.048
129.342
1.00
97.79
ATOM
2325
CB
ASN
G
448
99.908
−149.848
130.235
1.00
102.67
ATOM
2326
CG
ASN
G
448
100.039
−151.126
131.038
1.00
103.58
ATOM
2327
OD1
ASN
G
448
101.140
−151.519
131.422
1.00
103.71
ATOM
2328
ND2
ASN
G
448
98.912
−151.781
131.299
1.00
103.79
ATOM
2329
N
ILE
G
449
101.566
−146.804
130.294
1.00
94.94
ATOM
2330
CA
ILE
G
449
101.935
−145.676
129.449
1.00
92.96
ATOM
2331
C
ILE
G
449
102.228
−146.206
128.054
1.00
92.14
ATOM
2332
O
ILE
G
449
103.343
−146.635
127.757
1.00
91.85
ATOM
2333
CB
ILE
G
449
103.182
−144.975
129.987
1.00
93.15
ATOM
2334
CG1
ILE
G
449
102.947
−144.584
131.449
1.00
94.25
ATOM
2335
CG2
ILE
G
449
103.494
−143.747
129.141
1.00
91.79
ATOM
2336
CD1
ILE
G
449
104.181
−144.084
132.146
1.00
94.95
ATOM
2337
N
THR
G
450
101.214
−146.178
127.201
1.00
91.70
ATOM
2338
CA
THR
G
450
101.349
−146.681
125.845
1.00
92.19
ATOM
2339
C
THR
G
450
101.910
−145.647
124.876
1.00
91.91
ATOM
2340
O
THR
G
450
102.164
−145.955
123.714
1.00
92.23
ATOM
2341
CB
THR
G
450
99.992
−147.171
125.312
1.00
92.87
ATOM
2342
OG1
THR
G
450
99.044
−146.101
125.374
1.00
94.60
ATOM
2343
CG2
THR
G
450
99.480
−148.328
126.147
1.00
91.70
ATOM
2344
N
GLY
G
451
102.101
−144.421
125.350
1.00
92.40
ATOM
2345
CA
GLY
G
451
102.631
−143.373
124.493
1.00
93.12
ATOM
2346
C
GLY
G
451
102.795
−142.059
125.232
1.00
93.74
ATOM
2347
O
GLY
G
451
102.551
−141.983
126.434
1.00
94.94
ATOM
2348
N
LEU
G
452
103.208
−141.020
124.516
1.00
93.32
ATOM
2349
CA
LEU
G
452
103.394
−139.708
125.121
1.00
94.48
ATOM
2350
C
LEU
G
452
103.370
−138.597
124.077
1.00
96.43
ATOM
2351
O
LEU
G
452
103.383
−138.862
122.875
1.00
97.24
ATOM
2352
CB
LEU
G
452
104.717
−139.660
125.898
1.00
94.99
ATOM
2353
CG
LEU
G
452
105.989
−140.116
125.174
1.00
94.35
ATOM
2354
CD1
LEU
G
452
107.082
−139.061
125.305
1.00
93.41
ATOM
2355
CD2
LEU
G
452
106.447
−141.441
125.767
1.00
94.53
ATOM
2356
N
LEU
G
453
103.339
−137.353
124.546
1.00
97.31
ATOM
2357
CA
LEU
G
453
103.312
−136.191
123.662
1.00
97.97
ATOM
2358
C
LEU
G
453
104.537
−135.317
123.900
1.00
99.02
ATOM
2359
O
LEU
G
453
104.923
−135.080
125.044
1.00
98.34
ATOM
2360
CB
LEU
G
453
102.045
−135.374
123.919
1.00
100.23
ATOM
2361
CG
LEU
G
453
100.710
−136.088
123.684
1.00
102.44
ATOM
2362
CD1
LEU
G
453
99.780
−135.831
124.857
1.00
104.66
ATOM
2363
CD2
LEU
G
453
100.089
−135.602
122.384
1.00
104.74
ATOM
2364
N
LEU
G
454
105.144
−134.835
122.821
1.00
101.32
ATOM
2365
CA
LEU
G
454
106.335
−133.995
122.925
1.00
104.16
ATOM
2366
C
LEU
G
454
106.287
−132.786
122.002
1.00
105.43
ATOM
2367
O
LEU
G
454
105.683
−132.829
120.935
1.00
104.92
ATOM
2368
CB
LEU
G
454
107.587
−134.810
122.590
1.00
107.11
ATOM
2369
CG
LEU
G
454
108.124
−135.787
123.640
1.00
109.52
ATOM
2370
CD1
LEU
G
454
109.036
−136.808
122.980
1.00
110.38
ATOM
2371
CD2
LEU
G
454
108.870
−135.011
124.718
1.00
110.90
ATOM
2372
N
THR
G
455
106.940
−131.710
122.423
1.00
107.87
ATOM
2373
CA
THR
G
455
107.007
−130.483
121.639
1.00
111.93
ATOM
2374
C
THR
G
455
108.450
−129.979
121.669
1.00
113.34
ATOM
2375
O
THR
G
455
108.941
−129.532
122.708
1.00
113.32
ATOM
2376
CB
THR
G
455
106.087
−129.392
122.216
1.00
112.59
ATOM
2377
OG1
THR
G
455
106.172
−129.403
123.643
1.00
113.78
ATOM
2378
CG2
THR
G
455
104.650
−129.615
121.796
1.00
113.67
ATOM
2379
N
ARG
G
456
109.126
−130.057
120.526
1.00
115.82
ATOM
2380
CA
ARG
G
456
110.520
−129.638
120.426
1.00
117.80
ATOM
2381
C
ARG
G
456
110.714
−128.126
120.336
1.00
118.96
ATOM
2382
O
ARG
G
456
109.853
−127.405
119.834
1.00
118.29
ATOM
2383
CB
ARG
G
456
111.177
−130.305
119.212
1.00
117.97
ATOM
2384
CG
ARG
G
456
110.748
−129.740
117.864
1.00
119.08
ATOM
2385
CD
ARG
G
456
111.533
−130.384
116.728
1.00
119.35
ATOM
2386
NE
ARG
G
456
111.439
−129.607
115.496
1.00
119.68
ATOM
2387
CZ
ARG
G
456
112.130
−128.496
115.257
1.00
119.75
ATOM
2388
NH1
ARG
G
456
112.977
−128.027
116.165
1.00
120.37
ATOM
2389
NH2
ARG
G
456
111.968
−127.847
114.112
1.00
119.93
ATOM
2390
N
ASP
G
457
111.860
−127.656
120.823
1.00
119.85
ATOM
2391
CA
ASP
G
457
112.189
−126.233
120.793
1.00
120.75
ATOM
2392
C
ASP
G
457
112.749
−125.857
119.427
1.00
122.23
ATOM
2393
O
ASP
G
457
113.723
−126.451
118.964
1.00
122.14
ATOM
2394
CB
ASP
G
457
113.226
−125.903
121.869
1.00
120.14
ATOM
2395
CG
ASP
G
457
112.739
−126.229
123.267
1.00
120.03
ATOM
2396
OD1
ASP
G
457
113.374
−125.778
124.243
1.00
119.43
ATOM
2397
OD2
ASP
G
457
111.721
−126.943
123.378
1.00
119.90
ATOM
2398
N
GLY
G
458
112.139
−124.865
118.787
1.00
123.91
ATOM
2399
CA
GLY
G
458
112.597
−124.440
117.475
1.00
126.39
ATOM
2400
C
GLY
G
458
113.689
−123.387
117.531
1.00
128.56
ATOM
2401
O
GLY
G
458
114.703
−123.567
118.205
1.00
128.30
ATOM
2402
N
GLY
G
459
113.487
−122.284
116.817
1.00
130.42
ATOM
2403
CA
GLY
G
459
114.472
−121.222
116.807
1.00
132.58
ATOM
2404
C
GLY
G
459
115.502
−121.403
115.712
1.00
134.70
ATOM
2405
O
GLY
G
459
116.070
−122.485
115.552
1.00
134.58
ATOM
2406
N
ILE
G
460
115.751
−120.338
114.959
1.00
137.83
ATOM
2407
CA
ILE
G
460
116.726
−120.379
113.875
1.00
140.76
ATOM
2408
C
ILE
G
460
118.138
−120.321
114.468
1.00
142.81
ATOM
2409
O
ILE
G
460
119.123
−120.606
113.792
1.00
142.92
ATOM
2410
CB
ILE
G
460
116.497
−119.194
112.903
1.00
140.96
ATOM
2411
CG1
ILE
G
460
116.933
−119.570
111.484
1.00
141.22
ATOM
2412
CG2
ILE
G
460
117.259
−117.970
113.383
1.00
141.19
ATOM
2413
CD1
ILE
G
460
118.421
−119.766
111.310
1.00
140.88
ATOM
2414
N
ASN
G
461
118.223
−119.963
115.746
1.00
145.09
ATOM
2415
CA
ASN
G
461
119.506
−119.878
116.443
1.00
147.66
ATOM
2416
C
ASN
G
461
120.070
−121.289
116.632
1.00
149.02
ATOM
2417
O
ASN
G
461
119.393
−122.161
117.178
1.00
148.11
ATOM
2418
CB
ASN
G
461
119.309
−119.186
117.800
1.00
148.39
ATOM
2419
CG
ASN
G
461
120.581
−118.560
118.329
1.00
149.53
ATOM
2420
OD1
ASN
G
461
121.509
−119.257
118.737
1.00
149.19
ATOM
2421
ND2
ASN
G
461
120.631
−117.233
118.323
1.00
148.79
ATOM
2422
N
GLU
G
462
121.303
−121.511
116.179
1.00
151.28
ATOM
2423
CA
GLU
G
462
121.931
−122.826
116.284
1.00
153.22
ATOM
2424
C
GLU
G
462
122.706
−123.073
117.578
1.00
153.57
ATOM
2425
O
GLU
G
462
123.216
−122.143
118.202
1.00
153.46
ATOM
2426
CB
GLU
G
462
122.859
−123.067
115.085
1.00
153.86
ATOM
2427
CG
GLU
G
462
124.074
−122.139
114.989
1.00
156.71
ATOM
2428
CD
GLU
G
462
123.763
−120.798
114.342
1.00
157.61
ATOM
2429
OE1
GLU
G
462
123.171
−119.922
115.006
1.00
157.89
ATOM
2430
OE2
GLU
G
462
124.110
−120.625
113.154
1.00
158.13
ATOM
2431
N
ASN
G
463
122.794
−124.342
117.965
1.00
153.66
ATOM
2432
CA
ASN
G
463
123.507
−124.735
119.172
1.00
153.40
ATOM
2433
C
ASN
G
463
123.918
−126.200
119.044
1.00
152.49
ATOM
2434
O
ASN
G
463
124.772
−126.690
119.784
1.00
152.48
ATOM
2435
CB
ASN
G
463
122.608
−124.525
120.400
1.00
154.12
ATOM
2436
CG
ASN
G
463
123.375
−124.598
121.707
1.00
155.58
ATOM
2437
OD1
ASN
G
463
123.613
−125.679
122.245
1.00
156.54
ATOM
2438
ND2
ASN
G
463
123.780
−123.439
122.217
1.00
156.41
ATOM
2439
N
GLY
G
464
123.311
−126.886
118.081
1.00
150.94
ATOM
2440
CA
GLY
G
464
123.614
−128.286
117.858
1.00
149.00
ATOM
2441
C
GLY
G
464
122.693
−129.184
118.658
1.00
147.53
ATOM
2442
O
GLY
G
464
122.652
−130.397
118.450
1.00
147.66
ATOM
2443
N
THR
G
465
121.937
−128.577
119.566
1.00
145.51
ATOM
2444
CA
THR
G
465
121.012
−129.311
120.416
1.00
142.98
ATOM
2445
C
THR
G
465
119.561
−128.931
120.146
1.00
140.93
ATOM
2446
O
THR
G
465
119.208
−127.752
120.074
1.00
140.82
ATOM
2447
CB
THR
G
465
121.305
−129.042
121.903
1.00
143.71
ATOM
2448
OG1
THR
G
465
121.216
−127.633
122.153
1.00
144.71
ATOM
2449
CG2
THR
G
465
122.691
−129.520
122.266
1.00
143.31
ATOM
2450
N
GLU
G
466
118.730
−129.951
119.981
1.00
137.84
ATOM
2451
CA
GLU
G
466
117.304
−129.762
119.750
1.00
134.60
ATOM
2452
C
GLU
G
466
116.586
−130.315
120.976
1.00
132.23
ATOM
2453
O
GLU
G
466
116.495
−131.530
121.155
1.00
131.65
ATOM
2454
CB
GLU
G
466
116.866
−130.515
118.492
1.00
134.81
ATOM
2455
CG
GLU
G
466
117.430
−129.969
117.182
1.00
135.55
ATOM
2456
CD
GLU
G
466
116.756
−128.681
116.729
1.00
136.34
ATOM
2457
OE1
GLU
G
466
117.195
−128.100
115.711
1.00
136.05
ATOM
2458
OE2
GLU
G
466
115.785
−128.250
117.386
1.00
137.26
ATOM
2459
N
ILE
G
467
116.080
−129.417
121.814
1.00
129.25
ATOM
2460
CA
ILE
G
467
115.400
−129.801
123.047
1.00
126.01
ATOM
2461
C
ILE
G
467
113.989
−130.338
122.826
1.00
123.54
ATOM
2462
O
ILE
G
467
113.261
−129.848
121.966
1.00
122.31
ATOM
2463
CB
ILE
G
467
115.299
−128.602
124.008
1.00
125.82
ATOM
2464
CG1
ILE
G
467
116.509
−127.686
123.827
1.00
125.39
ATOM
2465
CG2
ILE
G
467
115.262
−129.091
125.449
1.00
124.63
ATOM
2466
CD1
ILE
G
467
117.829
−128.361
124.104
1.00
125.46
ATOM
2467
N
PHE
G
468
113.609
−131.345
123.610
1.00
121.29
ATOM
2468
CA
PHE
G
468
112.277
−131.939
123.518
1.00
119.38
ATOM
2469
C
PHE
G
468
111.562
−131.923
124.866
1.00
117.84
ATOM
2470
O
PHE
G
468
111.904
−132.687
125.768
1.00
118.28
ATOM
2471
CB
PHE
G
468
112.360
−133.382
123.005
1.00
119.43
ATOM
2472
CG
PHE
G
468
112.625
−133.488
121.533
1.00
119.45
ATOM
2473
CD1
PHE
G
468
113.909
−133.319
121.028
1.00
119.08
ATOM
2474
CD2
PHE
G
468
111.584
−133.738
120.645
1.00
119.65
ATOM
2475
CE1
PHE
G
468
114.154
−133.397
119.660
1.00
119.36
ATOM
2476
CE2
PHE
G
468
111.818
−133.817
119.274
1.00
119.82
ATOM
2477
CZ
PHE
G
468
113.105
−133.647
118.781
1.00
119.73
ATOM
2478
N
ARG
G
469
110.564
−131.053
124.991
1.00
115.90
ATOM
2479
CA
ARG
G
469
109.789
−130.924
126.224
1.00
113.44
ATOM
2480
C
ARG
G
469
108.427
−131.610
126.079
1.00
112.22
ATOM
2481
O
ARG
G
469
107.896
−131.719
124.975
1.00
112.65
ATOM
2482
CB
ARG
G
469
109.598
−129.441
126.557
1.00
113.09
ATOM
2483
CG
ARG
G
469
110.898
−128.670
126.770
1.00
111.90
ATOM
2484
CD
ARG
G
469
110.656
−127.167
126.817
1.00
111.27
ATOM
2485
NE
ARG
G
469
111.891
−126.413
127.024
1.00
110.94
ATOM
2486
CZ
ARG
G
469
112.337
−126.009
128.210
1.00
111.59
ATOM
2487
NH1
ARG
G
469
111.650
−126.282
129.311
1.00
111.63
ATOM
2488
NH2
ARG
G
469
113.474
−125.331
128.297
1.00
111.19
ATOM
2489
N
PRO
G
470
107.846
−132.080
127.196
1.00
110.32
ATOM
2490
CA
PRO
G
470
106.544
−132.757
127.180
1.00
109.56
ATOM
2491
C
PRO
G
470
105.415
−131.804
126.802
1.00
109.38
ATOM
2492
O
PRO
G
470
105.184
−130.810
127.487
1.00
109.40
ATOM
2493
CB
PRO
G
470
106.404
−133.268
128.615
1.00
108.27
ATOM
2494
CG
PRO
G
470
107.830
−133.391
129.083
1.00
109.61
ATOM
2495
CD
PRO
G
470
108.422
−132.120
128.547
1.00
110.06
ATOM
2496
N
GLY
G
471
104.716
−132.104
125.712
1.00
109.49
ATOM
2497
CA
GLY
G
471
103.619
−131.252
125.285
1.00
109.11
ATOM
2498
C
GLY
G
471
102.315
−131.685
125.924
1.00
108.92
ATOM
2499
O
GLY
G
471
102.257
−131.939
127.126
1.00
108.60
ATOM
2500
N
GLY
G
472
101.265
−131.772
125.119
1.00
109.42
ATOM
2501
CA
GLY
G
472
99.979
−132.193
125.638
1.00
110.45
ATOM
2502
C
GLY
G
472
99.070
−131.040
126.004
1.00
111.45
ATOM
2503
O
GLY
G
472
99.502
−129.891
126.097
1.00
111.96
ATOM
2504
N
GLY
G
473
97.796
−131.351
126.209
1.00
111.01
ATOM
2505
CA
GLY
G
473
96.835
−130.322
126.562
1.00
110.43
ATOM
2506
C
GLY
G
473
95.576
−130.471
125.741
1.00
109.88
ATOM
2507
O
GLY
G
473
94.491
−130.678
126.277
1.00
109.70
ATOM
2508
N
ASP
G
474
95.730
−130.366
124.428
1.00
109.83
ATOM
2509
CA
ASP
G
474
94.608
−130.513
123.516
1.00
110.37
ATOM
2510
C
ASP
G
474
94.250
−131.993
123.454
1.00
110.43
ATOM
2511
O
ASP
G
474
95.003
−132.796
122.907
1.00
110.70
ATOM
2512
CB
ASP
G
474
94.996
−129.990
122.135
1.00
111.19
ATOM
2513
CG
ASP
G
474
93.885
−130.137
121.121
1.00
111.06
ATOM
2514
OD1
ASP
G
474
92.726
−129.834
121.465
1.00
110.92
ATOM
2515
OD2
ASP
G
474
94.180
−130.541
119.977
1.00
111.81
ATOM
2516
N
MET
G
475
93.102
−132.346
124.024
1.00
109.99
ATOM
2517
CA
MET
G
475
92.659
−133.732
124.061
1.00
108.99
ATOM
2518
C
MET
G
475
92.325
−134.343
122.706
1.00
108.30
ATOM
2519
O
MET
G
475
91.989
−135.524
122.634
1.00
108.27
ATOM
2520
CB
MET
G
475
91.454
−133.873
124.992
1.00
110.06
ATOM
2521
CG
MET
G
475
91.742
−133.498
126.443
1.00
110.69
ATOM
2522
SD
MET
G
475
93.014
−134.548
127.161
1.00
111.79
ATOM
2523
CE
MET
G
475
93.387
−133.671
128.688
1.00
111.72
ATOM
2524
N
ARG
G
476
92.409
−133.560
121.633
1.00
107.84
ATOM
2525
CA
ARG
G
476
92.113
−134.093
120.302
1.00
107.39
ATOM
2526
C
ARG
G
476
93.218
−135.060
119.904
1.00
105.79
ATOM
2527
O
ARG
G
476
92.979
−136.056
119.224
1.00
105.68
ATOM
2528
CB
ARG
G
476
92.034
−132.961
119.271
1.00
108.90
ATOM
2529
CG
ARG
G
476
90.927
−131.951
119.512
1.00
110.95
ATOM
2530
CD
ARG
G
476
91.060
−130.754
118.578
1.00
112.58
ATOM
2531
NE
ARG
G
476
90.086
−129.707
118.883
1.00
114.24
ATOM
2532
CZ
ARG
G
476
90.079
−128.499
118.323
1.00
115.25
ATOM
2533
NH1
ARG
G
476
90.997
−128.170
117.422
1.00
114.91
ATOM
2534
NH2
ARG
G
476
89.151
−127.616
118.668
1.00
115.36
ATOM
2535
N
ASP
G
477
94.430
−134.748
120.345
1.00
103.73
ATOM
2536
CA
ASP
G
477
95.599
−135.558
120.051
1.00
101.54
ATOM
2537
C
ASP
G
477
95.552
−136.903
120.752
1.00
99.60
ATOM
2538
O
ASP
G
477
96.155
−137.864
120.286
1.00
98.87
ATOM
2539
CB
ASP
G
477
96.863
−134.813
120.473
1.00
103.36
ATOM
2540
CG
ASP
G
477
96.918
−133.399
119.918
1.00
105.17
ATOM
2541
OD1
ASP
G
477
96.905
−133.252
118.680
1.00
105.96
ATOM
2542
OD2
ASP
G
477
96.965
−132.441
120.720
1.00
106.74
ATOM
2543
N
ASN
G
478
94.844
−136.972
121.875
1.00
98.58
ATOM
2544
CA
ASN
G
478
94.741
−138.220
122.628
1.00
98.61
ATOM
2545
C
ASN
G
478
93.974
−139.286
121.862
1.00
99.30
ATOM
2546
O
ASN
G
478
94.303
−140.468
121.926
1.00
99.94
ATOM
2547
CB
ASN
G
478
94.058
−137.984
123.977
1.00
97.49
ATOM
2548
CG
ASN
G
478
94.911
−137.180
124.928
1.00
96.81
ATOM
2549
OD1
ASN
G
478
95.228
−136.022
124.666
1.00
95.84
ATOM
2550
ND2
ASN
G
478
95.289
−137.792
126.044
1.00
97.25
ATOM
2551
N
TRP
G
479
92.945
−138.861
121.141
1.00
99.87
ATOM
2552
CA
TRP
G
479
92.131
−139.788
120.370
1.00
100.66
ATOM
2553
C
TRP
G
479
92.738
−139.936
118.980
1.00
102.34
ATOM
2554
O
TRP
G
479
92.442
−140.887
118.259
1.00
102.87
ATOM
2555
CB
TRP
G
479
90.692
−139.267
120.263
1.00
98.97
ATOM
2556
CG
TRP
G
479
90.253
−138.426
121.434
1.00
96.33
ATOM
2557
CD1
TRP
G
479
89.768
−137.150
121.384
1.00
94.67
ATOM
2558
CD2
TRP
G
479
90.275
−138.791
122.823
1.00
94.42
ATOM
2559
NE1
TRP
G
479
89.491
−136.696
122.651
1.00
92.78
ATOM
2560
CE2
TRP
G
479
89.795
−137.680
123.553
1.00
92.98
ATOM
2561
CE3
TRP
G
479
90.660
−139.944
123.520
1.00
93.84
ATOM
2562
CZ2
TRP
G
479
89.681
−137.691
124.948
1.00
92.68
ATOM
2563
CZ3
TRP
G
479
90.547
−139.954
124.910
1.00
93.85
ATOM
2564
CH2
TRP
G
479
90.063
−138.831
125.606
1.00
93.88
ATOM
2565
N
ARG
G
480
93.588
−138.984
118.607
1.00
103.86
ATOM
2566
CA
ARG
G
480
94.246
−139.015
117.304
1.00
105.08
ATOM
2567
C
ARG
G
480
95.281
−140.125
117.271
1.00
105.26
ATOM
2568
O
ARG
G
480
95.594
−140.668
116.215
1.00
105.84
ATOM
2569
CB
ARG
G
480
94.922
−137.670
117.013
1.00
106.56
ATOM
2570
CG
ARG
G
480
94.125
−136.768
116.090
1.00
107.60
ATOM
2571
CD
ARG
G
480
94.632
−135.333
116.100
1.00
109.95
ATOM
2572
NE
ARG
G
480
93.740
−134.452
115.346
1.00
114.38
ATOM
2573
CZ
ARG
G
480
93.766
−133.122
115.392
1.00
117.10
ATOM
2574
NH1
ARG
G
480
94.645
−132.492
116.162
1.00
118.14
ATOM
2575
NH2
ARG
G
480
92.901
−132.421
114.671
1.00
119.32
ATOM
2576
N
SER
G
481
95.807
−140.461
118.440
1.00
105.09
ATOM
2577
CA
SER
G
481
96.810
−141.506
118.545
1.00
105.78
ATOM
2578
C
SER
G
481
96.169
−142.872
118.346
1.00
106.98
ATOM
2579
O
SER
G
481
96.853
−143.854
118.069
1.00
107.51
ATOM
2580
CB
SER
G
481
97.483
−141.448
119.918
1.00
105.86
ATOM
2581
OG
SER
G
481
96.531
−141.636
120.949
1.00
102.63
ATOM
2582
N
GLU
G
482
94.850
−142.925
118.487
1.00
108.44
ATOM
2583
CA
GLU
G
482
94.112
−144.173
118.341
1.00
110.31
ATOM
2584
C
GLU
G
482
93.359
−144.249
117.016
1.00
111.16
ATOM
2585
O
GLU
G
482
93.213
−145.324
116.438
1.00
111.61
ATOM
2586
CB
GLU
G
482
93.123
−144.327
119.501
1.00
110.81
ATOM
2587
CG
GLU
G
482
93.759
−144.254
120.883
1.00
110.72
ATOM
2588
CD
GLU
G
482
94.577
−145.485
121.225
1.00
110.51
ATOM
2589
OE1
GLU
G
482
93.977
−146.563
121.425
1.00
109.50
ATOM
2590
OE2
GLU
G
482
95.819
−145.375
121.292
1.00
110.56
ATOM
2591
N
LEU
G
483
92.883
−143.103
116.540
1.00
111.84
ATOM
2592
CA
LEU
G
483
92.130
−143.046
115.294
1.00
112.60
ATOM
2593
C
LEU
G
483
92.979
−142.608
114.107
1.00
113.68
ATOM
2594
O
LEU
G
483
92.449
−142.122
113.108
1.00
114.27
ATOM
2595
CB
LEU
G
483
90.949
−142.083
115.440
1.00
112.17
ATOM
2596
CG
LEU
G
483
89.872
−142.442
116.469
1.00
111.13
ATOM
2597
CD1
LEU
G
483
88.927
−141.266
116.650
1.00
110.76
ATOM
2598
CD2
LEU
G
483
89.115
−143.677
116.003
1.00
111.73
ATOM
2599
N
TYR
G
484
94.292
−142.782
114.206
1.00
114.79
ATOM
2600
CA
TYR
G
484
95.186
−142.383
113.125
1.00
115.54
ATOM
2601
C
TYR
G
484
95.019
−143.284
111.912
1.00
115.88
ATOM
2602
O
TYR
G
484
95.102
−142.827
110.774
1.00
115.90
ATOM
2603
CB
TYR
G
484
96.644
−142.409
113.602
1.00
115.90
ATOM
2604
CG
TYR
G
484
97.250
−143.791
113.733
1.00
116.80
ATOM
2605
CD1
TYR
G
484
98.038
−144.328
112.714
1.00
116.77
ATOM
2606
CD2
TYR
G
484
97.042
−144.560
114.878
1.00
118.01
ATOM
2607
CE1
TYR
G
484
98.608
−145.597
112.836
1.00
117.84
ATOM
2608
CE2
TYR
G
484
97.606
−145.828
115.008
1.00
118.60
ATOM
2609
CZ
TYR
G
484
98.388
−146.339
113.985
1.00
118.39
ATOM
2610
OH
TYR
G
484
98.956
−147.587
114.115
1.00
118.31
ATOM
2611
N
LYS
G
485
94.780
−144.566
112.160
1.00
116.57
ATOM
2612
CA
LYS
G
485
94.606
−145.525
111.082
1.00
117.94
ATOM
2613
C
LYS
G
485
93.136
−145.765
110.752
1.00
119.33
ATOM
2614
O
LYS
G
485
92.749
−146.883
110.413
1.00
119.55
ATOM
2615
CB
LYS
G
485
95.282
−146.851
111.451
1.00
116.62
ATOM
2616
CG
LYS
G
485
94.855
−147.425
112.794
1.00
114.79
ATOM
2617
CD
LYS
G
485
95.577
−148.736
113.075
1.00
113.85
ATOM
2618
CE
LYS
G
485
95.207
−149.299
114.438
1.00
112.32
ATOM
2619
NZ
LYS
G
485
95.894
−150.593
114.708
1.00
112.53
ATOM
2620
N
TYR
G
486
92.321
−144.718
110.849
1.00
121.24
ATOM
2621
CA
TYR
G
486
90.895
−144.831
110.549
1.00
123.65
ATOM
2622
C
TYR
G
486
90.356
−143.638
109.763
1.00
125.80
ATOM
2623
O
TYR
G
486
90.761
−142.499
109.986
1.00
126.52
ATOM
2624
CB
TYR
G
486
90.077
−144.979
111.836
1.00
122.26
ATOM
2625
CG
TYR
G
486
90.279
−146.286
112.559
1.00
120.89
ATOM
2626
CD1
TYR
G
486
91.272
−146.426
113.527
1.00
120.39
ATOM
2627
CD2
TYR
G
486
89.478
−147.389
112.271
1.00
120.13
ATOM
2628
CE1
TYR
G
486
91.461
−147.636
114.192
1.00
119.39
ATOM
2629
CE2
TYR
G
486
89.660
−148.600
112.927
1.00
119.78
ATOM
2630
CZ
TYR
G
486
90.651
−148.717
113.885
1.00
119.20
ATOM
2631
OH
TYR
G
486
90.829
−149.916
114.531
1.00
118.81
ATOM
2632
N
LYS
G
487
89.433
−143.912
108.848
1.00
127.78
ATOM
2633
CA
LYS
G
487
88.820
−142.869
108.041
1.00
129.98
ATOM
2634
C
LYS
G
487
87.421
−143.315
107.641
1.00
131.14
ATOM
2635
O
LYS
G
487
87.261
−144.328
106.959
1.00
131.65
ATOM
2636
CB
LYS
G
487
89.660
−142.592
106.786
1.00
130.89
ATOM
2637
CG
LYS
G
487
89.250
−141.325
106.044
1.00
132.86
ATOM
2638
CD
LYS
G
487
90.086
−141.091
104.791
1.00
134.47
ATOM
2639
CE
LYS
G
487
89.712
−139.769
104.131
1.00
134.86
ATOM
2640
NZ
LYS
G
487
90.540
−139.468
102.931
1.00
133.70
ATOM
2641
N
VAL
G
488
86.408
−142.571
108.072
1.00
132.54
ATOM
2642
CA
VAL
G
488
85.031
−142.915
107.737
1.00
134.39
ATOM
2643
C
VAL
G
488
84.808
−142.655
106.245
1.00
135.42
ATOM
2644
O
VAL
G
488
85.382
−141.719
105.682
1.00
135.33
ATOM
2645
CB
VAL
G
488
84.047
−142.072
108.571
1.00
134.46
ATOM
2646
CG1
VAL
G
488
84.146
−140.608
108.170
1.00
134.65
ATOM
2647
CG2
VAL
G
488
82.638
−142.599
108.401
1.00
134.22
ATOM
2648
N
VAL
G
489
83.982
−143.470
105.600
1.00
137.04
ATOM
2649
CA
VAL
G
489
83.762
−143.293
104.173
1.00
139.05
ATOM
2650
C
VAL
G
489
82.330
−143.585
103.707
1.00
140.08
ATOM
2651
O
VAL
G
489
81.606
−144.357
104.338
1.00
140.02
ATOM
2652
CB
VAL
G
489
84.732
−144.207
103.383
1.00
139.34
ATOM
2653
CG1
VAL
G
489
83.998
−145.432
102.860
1.00
140.18
ATOM
2654
CG2
VAL
G
489
85.385
−143.422
102.267
1.00
139.74
ATOM
2655
N
LYS
G
490
81.934
−142.966
102.597
1.00
142.79
ATOM
2656
CA
LYS
G
490
80.607
−143.179
102.032
1.00
145.45
ATOM
2657
C
LYS
G
490
80.669
−144.502
101.281
1.00
147.18
ATOM
2658
O
LYS
G
490
81.655
−144.786
100.598
1.00
146.18
ATOM
2659
CB
LYS
G
490
80.247
−142.036
101.070
1.00
145.83
ATOM
2660
CG
LYS
G
490
78.752
−141.852
100.807
1.00
146.99
ATOM
2661
CD
LYS
G
490
78.501
−140.629
99.928
1.00
148.09
ATOM
2662
CE
LYS
G
490
77.034
−140.213
99.934
1.00
148.60
ATOM
2663
NZ
LYS
G
490
76.795
−138.971
99.143
1.00
149.62
ATOM
2664
N
ILE
G
491
79.626
−145.312
101.399
1.00
149.88
ATOM
2665
CA
ILE
G
491
79.617
−146.604
100.731
1.00
153.14
ATOM
2666
C
ILE
G
491
79.546
−146.484
99.202
1.00
154.50
ATOM
2667
O
ILE
G
491
78.688
−147.084
98.550
1.00
154.54
ATOM
2668
CB
ILE
G
491
78.451
−147.475
101.262
1.00
153.49
ATOM
2669
CG1
ILE
G
491
78.722
−148.946
100.955
1.00
154.55
ATOM
2670
CG2
ILE
G
491
77.126
−147.000
100.685
1.00
153.61
ATOM
2671
CD1
ILE
G
491
79.857
−149.529
101.778
1.00
154.67
ATOM
2672
N
GLU
G
492
80.465
−145.699
98.645
1.00
156.47
ATOM
2673
CA
GLU
G
492
80.561
−145.474
97.201
1.00
158.38
ATOM
2674
C
GLU
G
492
81.994
−145.101
96.827
1.00
159.02
ATOM
2675
O
GLU
G
492
82.890
−145.919
97.028
1.00
158.59
ATOM
2676
CB
GLU
G
492
79.624
−144.345
96.762
1.00
159.61
ATOM
2677
CG
GLU
G
492
78.521
−144.781
95.808
1.00
162.25
ATOM
2678
CD
GLU
G
492
77.654
−143.621
95.352
1.00
162.67
ATOM
2679
OE1
GLU
G
492
78.173
−142.729
94.645
1.00
163.05
ATOM
2680
OE2
GLU
G
492
76.455
−143.599
95.704
1.00
162.15
ATOM
2681
OXT
GLU
G
492
82.208
−143.994
96.336
1.00
158.19
TER
2682
GLU
G
492
END
The present disclosure also provides for a machine-readable data storage medium which comprises a data storage material encoded with machine readable data defined by the structure coordinates of a stabilized gp120 polypeptide or gp120 polypeptide with an extended V3 loop as define in Table 1 or Table 2 respectively, or a subset thereof, such as at least about 5, such at least about 10, at least about 20, at least about 30, at least at least about 40, at least about 50, at least about 60, at least about 70, at least about 80, at least about 90, at least about 100, at least about 150, at least about 200, at least about 250, at least about 300, at least about 350, at least about 400, at least about 450, at least about 500 or more atoms of the structure, such as defined by the coordinates of Table 1 or Table 2.
Those of skill in the art will understand that a set of structure coordinates for a gp120 polypeptide, for example a stabilized gp120 polypeptide, a gp120 polypeptide with an extended V3 loop, or a portion thereof, is a relative set of points that define a shape in three dimensions. Thus, it is possible that an entirely different set of coordinates could define a similar or identical shape. Moreover, slight variations in the individual coordinates will have little effect on overall shape. The variations in coordinates discussed above may be generated because of mathematical manipulations of the structure coordinates. For example, the structure coordinates set forth in Table 1 or Table 2, or a portion thereof could be manipulated by crystallographic permutations of the structure coordinates, fractionalization of the structure coordinates; integer additions or subtractions to sets of the structure coordinates, deletion of a portion of the coordinates, inversion of the structure coordinates, or any combination of the above.
This disclosure further provides systems, such as computer systems, intended to generate structures and/or perform rational drug or compound design for an antigenic compound capable of eliciting an immune response in a subject. The system can contain one or more or all of: atomic co-ordinate data according to Table 1, Table 2, or a subset thereof and the Figures derived therefrom by homology modeling, the data defining the three-dimensional structure of a gp120 or at least one sub-domain thereof, or structure factor data for gp120, the structure factor data being derivable from the atomic co-ordinate data of Table 1 or Table 2 or a subset thereof and the Figures. This disclosure also involves computer readable media with: atomic co-ordinate data according to Table 1, Table 2 or a subset thereof and/or the Figures or derived therefrom by homology modeling, the data defining the three-dimensional structure of a gp120 or at least one sub-domain thereof; or structure factor data for a gp120, the structure factor data being derivable from the atomic co-ordinate data of Table 1, Table 2, or a subset thereof and/or the Figures. By providing such computer readable media, the atomic co-ordinate data can be routinely accessed to the gp120 or a sub-domain thereof. For example RASMOL (Sayle et al., TIBS vol. 20 (1995), 374) is a publicly available software package which allows access and analysis of atomic co-ordinate data for structural determination and/or rational drug design. Structure factor data, which are derivable from atomic co-ordinate data (see, for example, Blundell et al., in Protein Crystallography, Academic Press, NY, London and San Francisco (1976)), are particularly useful for calculating electron density maps, for example, difference Fourier electron density maps. Thus, there are additional uses for the computer readable media and/or computer systems and/or atomic co-ordinate data and additional reasons to provide them to users.
VIII. Identification of Immunogens
The crystals of this disclosure and particularly the atomic structure coordinates obtained from these crystals are particularly useful for identifying compounds elicit neutralizing antibodies, for example CD4BS and CD4i antibodies. The compounds identified are useful in eliciting antibodies to gp120, such as antibodies to lentivirus, such as SIV, or HIV, for example HIV-1 or HIV-2.
The crystal structure of a stabilized form of gp120 or a gp120 with the V3 loop in the extended conformation allows a novel approach for drug or compound discovery, identification, and design of compounds that mimic the antigenic surfaces of gp120 that bind neutralizing antibodies. Such compound can be useful as immunogens to illicit an immune response to HIV when administered to a subject, for example by eliciting anti-HIV antibodies, such as neutralizing antibodies, for example CD4BD or CD4i antibodies. Compounds that elicit anti-HIV antibodies are useful in diagnosis, treatment, or prevention of HIV-1 in a subject in need thereof.
The disclosure provides a computer-based method of rational drug, compound design, or identification which comprises: providing the structure of a stabilized form of gp120 (for example as defined by the coordinates or a subset of the coordinates in Table 1 and/or in the Figures) or a gp120 with the V3 loop in the extended conformation (for example as defined by the coordinates or subset of the coordinates in Table 2 and/or in the Figures); providing a structure of a candidate compound; and fitting the structure of the candidate compound to the structure of the stabilized form of gp120 (for example as defined by the coordinates or a subset of the coordinates in Table 1 and/or in the Figures) or the gp120 with the V3 loop in the extended conformation (for example as defined by the coordinates or a subset of the coordinates in Table 2 and/or in the Figures.
In certain embodiments, the coordinates of atoms of interest of the stabilized form of gp120 or the gp120 with the V3 loop in the extended conformation in the vicinity of the antigenic surface are used to model the antigenic surface to which as antibody binds, such as a neutralizing antibody, for example a CD4i or CD4BS antibody. These coordinates may be used to define a space which is then screened “in silico” against a candidate compound. Thus, the disclosure provides a computer-based method of rational drug or compound design or identification which comprises: providing the coordinates of at least two atoms of Table 1 or Table 2; providing the structure of a candidate compound; and fitting the structure of the candidate to the coordinates of at least two atoms of Table 1 or Table 2.
In practice, it may be desirable to model a sufficient number of atoms of the stabilized form of gp120 or the gp120 with the V3 loop in the extended conformation as defined by the coordinates of Table 1 or Table 2 which represent the active site or binding region. Thus, there can be provided the coordinates of at least about 5, such at least about 10, at least about 20, at least about 30, at least at least about 40, at least about 50, at least about 60, at least about 70, at least about 80, at least about 90, at least about 100, at least about 150, at least about 200, at least about 250, at least about 300, at least about 350, at least about 400, at least about 450, or at least about 500 atoms of the structure.
The methods disclosed herein can employ a sub-domain, region, or fragment of interest of the stabilized form of gp120 or the gp120 with the extended V3 loop which is in the vicinity of the antigenic surface, and providing a computer-based method for identifying or rationally designing a compound or drug, such as an immunogen which includes: providing the coordinates of at least a sub-domain, region, or fragment of the stabilized form of gp120 or the gp120 with the extended V3 loop; providing the structure of a candidate compound that mimics the antigenic surface of the gp120 with the extended V3 loop; and fitting the structure of the candidate compound to the coordinates of the stabilized form of gp120 or the gp120 with the extended V3 loop sub-domain, region, or fragment provided. A “sub-domain”, “region”, or “fragment” can mean at least one, for example, one, two, three, four, or more, element(s) of secondary structure of particular regions of the stabilized form of gp120 or the gp120 with the extended V3 loop gp120 with the extended V3 loop, and includes those set forth in Table 1 and Table 2.
These methods can optionally include synthesizing the candidate compound, (such as an immunogen) and/or administering the candidate compound to an animal capable of eliciting antibodies and testing whether the candidate compound elicits anti-HIV antibodies. Compounds which elicit anti-HIV antibodies are useful for diagnostic purposes, as well as for immunogenic, immunological or even vaccine compositions, as well as pharmaceutical compositions.
In some embodiments, the candidate compound is designed from the gp120 amino acid sequence, for example an amino acid sequence is assembled to provide a candidate compound, for example by synthesizing the amino acid sequence or producing a nucleic acid encoding the candidate compound.
The step of providing the structure of a candidate compound may involve selecting the candidate compound by computationally screening a database of compounds for surface similarity with an epitope on the stabilized form of gp120 or the gp120 with the extended V3 loop. For example, a 3-D descriptor for the candidate compound may be derived, the descriptor including geometric and functional constraints derived from the architecture and chemical nature of the epitope. The descriptor may then be used to interrogate the compound database, a candidate compound being a compound that has a good match to the features of the descriptor. In effect, the descriptor can be a type of virtual pharmacophore.
The determination of the three-dimensional structure of the gp120 with the extended V3 loop provides a basis for the design of new and specific compounds that are useful for eliciting an immune response. For example, from knowing the three-dimensional structure the stabilized form of gp120 or the gp120 with the extended V3 loop, computer modeling programs may be used to design or identify different molecules expected to interact with possible or confirmed active sites such as binding sites or other structural or functional features of neutralizing antibodies.
By way of example, a compound that potentially mimics the antigenic surface of the stabilized form of gp120 or the gp120 with the extended V3 loop can be examined through the use of computer modeling using a docking program such as GRAM, DOCK or AUTODOCK (see for example, Walters et al. Drug Discovery Today, 3(4):160-178, 1998; Dunbrack et al. Folding and Design 2:27-42, 1997). This procedure can include computer fitting of potential immunogens to ascertain how well the shape and the chemical structure of the potential binder will mimic the antigenic surface. Various other computer programs such as AMBER or CHARM may be used to further refine the dynamic and electrostatic characteristics of a candidate compound. Programs such as GRID (Goodford, J. Med. Chem, 28:849-57, 1985) may also be used to analyze the antigenic surfaces to predict immunogenic compounds. Alternatively, computer-assisted, manual examination can be used to predict immunogenic compounds from antigenic surfaces.
IX. Stabilized gp120 Polypeptides as Crystallization Tools
One problem with the formation of crystals containing wild-type gp120 is that conformationally variable molecules are not amenable to crystallization. For an ordered crystal to form the molecules forming the crystal must be essential locked in place. Molecules that are unstable or “floppy” such as wild-type gp120 must overcome large entropic (ΔS) costs to form a crystal lattice. By using conformationally stabilized forms of gp120 this entropic cost of becoming ordered is lessened and crystals form more easily. Those skilled in the art can take advantage of this by crystallizing their complex of interest with a stabilized form of gp120. For example, stabilized forms of gp120 can be used to crystallize previously uncrystallizable broadly neutralizing antibodies. In one embodiment, the broadly neutralizing antibody does not induce conformational stabilization as measured by −TΔS of less than 28 kcal/mol upon antibody binding to gp120. The use of broadly neutralizing antibodies is disclosed, for example, in Burton, Nature Re. 2:706-713, 2002, herein incorporated by reference. One example of how this can be accomplished is by forming complexes of a stabilized form of gp120 and the antibody of interest in the presence of CD4.
The following examples are provided to illustrate certain particular features and/or embodiments. These examples should not be construed to limit the invention to the particular features or embodiments described.
This example describes the methods used to design stabilized forms of gp120 disclosed herein.
Thermodynamic analysis showed that the conformation of gp120 prior to CD4 binding was highly flexible (Myszka et al., Proc Natl Acad Sci USA. 97(16):9026-31, 2000). The CD4-bound state of gp120 consists of an inner domain (containing the N and C termini), an outer domain, and a four-stranded bridging sheet minidomain. Two-thirds of the CD4 contact surface is with the outer domain, the remaining one-third with the bridging sheet. In the unliganded state, the inner domain is radically altered, with most of its secondary structural elements repositioned. The bridging sheet is pulled apart with the two β-hairpins of the sheet separated by 20 Å. The outer domain, by contrast, remains virtually unchanged.
An initial series of mutants was constructed and analyzed. Initial antigenic analysis suggested that a single mutation, 375 S to W, was able to partially stabilize gp120 in the CD4-bound state. Thermodynamic analysis (ITC) confirmed this result, showing that the entropy (−TΔS) of gp120 binding to CD4 had reduced from 40 kcal/mol to roughly 25 kcal/mol (Xiang et al., J Virol. 76(19):9888-99, 2002).
To further reduce the entropy of CD4 binding to a range typical of antibody recognition (5-10 kcal/mol), precise characterization was used to confirm the mutational stabilization of conformation including: (1) crystallographic determination of the gp120 mutant structure (2) isothermotitration calorimetric analysis of the entropy of CD4 binding, and (3) precise surface-plasmon resonance analysis of the on/off rates of antibodies to the modified gp120 glycoproteins. This design cycle is shown in
Additional cavity-filling mutations and five different disulfides were modeled. The cavity-filling mutants increased hydrophobic interactions at domain interfaces. The disulfides either tied together the inner domain, outer domain and bridging sheet, or were internal to the bridging sheet. Crystallographic analysis on five of these disulfides showed that four of them formed disulfide bonds. Two of these showed minimal perturbation in structure: 96-275 which tied together the inner and outer domain, 109-428 which tied together the bridging sheet and outer domain. The 231-267 disulfide, which tied together the inner domain and outer domain and the 123-431 disulfide, which tied together two strands of the bridging sheet, both showed local perturbations of structure. The potential disulfide formed by mutating 231 to C and 268 to C did not form (
TABLE 3
Relative disulfide distances in the CD4-bound conformation
and in the unliganded SIV conformation.
Cα-Cα
Cα-Cα
Category
HIV Mutation
SIV Equivalent
Distance (Å)
Distance (Å)
Category
HIV Mutation
SIV Equivalent
HIV
SIV
S-S
96-275
78-290
6.4
21.9
S-S
109-428
91-441
6.1
16.2
S-S
123-431
105-444
4.4
23.5
S-S
231-267
245-282
6.0
16.8
Cavity
257/375
271/391
5.2
5.6
In the core context, each single inter-domain disulfide reduced the entropy of CD4 interaction by roughly 10 kcal/mol, as measured by isothermotitration calorimetry (ITC). Combinations of disulfides were tested. Two disulfide combinations showed similar antigenic phenotypes suggesting a partially stabilized gp120 conformation; ITC analysis for several of the different two disulfide combinations showed the entropy of CD4 interaction was reduced by roughly 20 kcal/mol. Combinations of three and four disulfides were also tested, although most of these only expressed poorly, perhaps due to complications of folding so many cysteines into the correct disulfide bonds. Removal of additional core disulfide (such as the second conserved disulfide in the V1/V2 region) and stabilization of the V3 region may enhance folding. A summary of the qualitative Biacore and ITC results for 17 mutants is shown in Table 4.
TABLE 4
Qualitative BIACORE on Supernatant and ITC results
Mutant location
Mutant
C1
CD4/CD4i
CD4BS
DSC/TM
Name
C2
C3
S1
S2
S3
S4
S5
CD4
17B
M6
b12
F105
F91
15e
m14
m18
SS
folding
° C.
WT
A
A
A
AA
AA
AA
AA
AA
AA
0
FFFF
50.6
core*
2a*
x
AAA
AA
AA
AA
N
N
A/N
A/N
AA
0
FFFF
50.6
4-0*
x
x
AAA
AA
AA
AA
N
N
A/N
A/N
AA
0
FFFF
55.7
4a*
x
x
A
A
nd
A/N
N
N
N
N
A
1
FFF
53.8
4b*
x
x
A
A
nd
AA
N
A/N
N
N
AA
1
FFF
56.4
4c*
x
x
A
A
nd
A
N
N
N
N
AA
1
FFF
5mut
x
x
A
A
nd
A
N
N
N
N
AA
1
FFF
6a*
x
x
x
A
A
nd
AA
N
A
N
N
AA
1
FFF
6b
x
x
x
AA
A
nd
N
N
N
N
N
N
2
FFF
59.0
8a
x
x
x
x
AA
A
nd
A
N
N
N
N
AA
2
F
8b*
x
x
x
x
AA
A
nd
A
N
N
N
N
A/N
2
FF
9a
x
x
x
x
x
A
N
N
A/N
N
N
N
N
N
3
F/N
8c
x
x
x
x
A
A
A
A/N
N
N
N
N
N
3
F/N
10a
x
x
x
x
x
N
N
nd
N
N
N
N
N
N
3
N
9b
x
x
x
x
A
A
A
A/N
N
N
N
N
AA
3
F/N
10c
x
x
x
x
x
A
N
N
A/N
N
N
N
N
AA
3
F/N
9c*
x
x
x
x
AA
AA
AAA
A
N
N
N
N
A/N
3
F
10b
x
x
x
x
x
A
A
A/N
A
N
N
N
N
A/N
3
F/N
11a
x
x
x
x
x
A
A
A
A
N
N
N
N
N
4
F/N
Note:
Cavity-filling mutants: C1: M95W, C2: T257S/S375W; C3: A433M; Disulfide bond mutants: S1: W96C/V275C; S2: I109C/Q428C; S3: T123C/G431C; S4: K231C/E267C; S5: K231C/E268C
Qualitative Biacore analysis and ITC of conformationally stabilized mutants. Biacore analyses were carried out on transfected cell supernatants or with purified protein at 10 ug/ml. Yellow rows represent mutants with structures determined by X-ray crystallography. “A” indicates binding, “F” indicates folding, and “N” indicates no binding or folding. The mutants are indicated with the wildtype residue and position followed by the substituted residue as follows, C1:M95W; C2:T275S/S375W; C3:A433M; S1:W96C/V275C; S2:I109C/Q428C; S3:T123C/G431C; S4K231C/E267C, for example A433M means that a methionine has been substituted for an alanine to create a C3 mutant protein.
Quantitative surface-plasmon resonance characterization of the binding of the various mutants to CD4, to 17b in the absence of CD4 and to 17b in the presence of CD4 allowed the degree of conformational stabilization to be assessed (Table 5).
TABLE 5
Quantitative Surface-Plasmon Resonance Characterization of Mutant gp120
Kinetic Parameters.
CD4
17b without CD4
17b with CD4
CD4
Mutant
on
off
KD
on
off
KD
on
off
KD
Induction
WT
4.95E+04
1.46E−03
2.95E−08
9.81E+03
4.33E−03
4.41E−07
7.84E+05
2.07E−03
2.64E−09
7.99E+01
core
2a
1.19E+05
1.78E−04
1.49E−09
1.03E+05
1.66E−02
1.61E−07
1.62E+06
9.98E−03
6.14E−09
1.57E+01
4-0
1.10E+05
1.39E−04
1.26E−09
1.54E+05
0.0196
1.28E−07
1.76E+06
0.0101
5.73E−09
1.14E+01
4a
1.23E+05
2.81E−04
2.28E−09
3.75E+05
0.0212
5.66E−08
2.51E+06
0.014
5.56E−09
6.69E+00
4b
1.08E+05
1.62E−04
1.50E−09
1.06E+05
0.0192
1.81E−07
1.48E+06
0.01
6.76E−09
1.40E+01
4c
l.07E+05
1.20E−04
1.12E−09
2.98E+05
0.0114
3.82E−08
2.05E+06
9.14E−03
4.45E−09
6.88E+00
5mut
3.08E+04
4.14E−04
1.35E−08
7.06E+04
0.0168
2.37E−07
1.31E+06
1.02E−02
7.78E−09
1.86E+01
6a
6.56E+04
4.47E−04
6.82E−09
8.94E+04
8.42E−03
9.41E−08
2.83E+05
7.46E−03
2.64E−08
3.17E+00
6b
7.89E+04
3.08E−04
3.91E−09
2.08E+05
0.0225
1.08E−07
9.27E+05
0.0126
1.36E−08
4.46E+00
8a
141000
0.00062
4.4E−09
354000
0.00712
2.01E−08
240000
0.0106
4.42E−08
0.677966
8b
83000
0.000484
5.83E−09
135000
0.00403
3.01E−08
310000
0.0151
4.88E−08
2.296296
9c
6.78E+04
1.45E−04
2.14E−09
1.04E+06
0.011
1.05E−08
1.28E+06
8.53E−03
6.69E−09
1.23E+00
CD4-on rate did not change much, indicating that initial CD4 occurs without conformational stabilization. The off-rate did decrease relative to wild-type, however, indicating that once CD4 bound, the conformational change was able to lock CD4 into place. A very different effect was seen with the CD4i antibody 17b. With 17b, conformational stabilization greatly increased the “on-rate” of binding, with little effect on the off-rate. This indicated that 17b cannot bind to its site, without the conformational change induced by CD4. In contrast, the initial binding even of CD4 must occur without the conformational change.
Surface-plasmon resonance (SPR) experiments were performed on a Biacore biosensor system at 25° C. Antibody (17b or m6 for the CD4i antibodies; F105, b12, 1.5e, etc. for CD4BS antibodies; b3, b3, b11 etc. for Fab fragments of CD4BS antibodies; and 2-domain CD4 for CD4) were immobilized on research grade CM5 sensor chips using the recommended standard amine coupling. Binding experiments were carried out in HBSP buffer (10 mM HEPES, pH 7.4, 150 mM NaCl and 0.005% surfactant P-20).
During the association phase, gp120 were passed over the buffer-equilibrated chip surface at a rate of 30 ul/min. After the association phase, bound analytes were allowed to dissociate for 5 min. The chip surface was then regenerated by two 25 ul injections of 10 mM Glycine/HCl (pH 3.0) at a flow rate of 50 ul/min. Association and dissociation values were calculated by numerical integration and global fitting to a 1:1 interaction model using BIAevaluation 3.0 software (Biacore, Inc.)
This example describes the methods used to obtain crystals of a gp120 with an extended V3 loop.
Variational Crystallization and Robotic Screening
To increase the probability of obtaining crystals suitable for X-ray structural analysis, 13 different complexes of HIV-1 envelope glycoprotein gp120 core with intact V3 were prepared and screened for crystallization. To ensure that gp120 was in its coreceptor binding conformation, all complexes contained CD4 (2-domain).
1) Protein Production, Purification, and Complex Preparation
Constructs of core+V3 gp120 from clade B HIV-1 isolates, YU2, JR-FL, and HXBc2, were prepared as previously described (Wu et al., Nature 384:179, 1996; Grundner et al., Virology 330:233, 2004). Truncations of the N-terminus, C-terminus, and substitution of the tripeptide GAG for the V1/V2 region were identical to those previously described (Grundner et al., Virology 330:233, 2004). Wild-type isolates were used for YU2 and HXBc2. For JR-FL, a functional 2-glycan deletion variant was used with mutations, 301N/Q and 388T/A (Koch et al., Virology 313:387, 2003). This CCR5-using JR-FL variant was more susceptible to neutralization by CD4-binding site antibodies, but not to CD4-induced antibodies (Koch et al., Virology 313: 387, 2003. Constructs were expressed in Drosophila Schneider 2 cells under an inducible metallothionein promoter. The 2-domain CD4 (d1d2), antigen-binding fragments (Fabs) and single-chain variable fragments (scFv) of CD4-induced (CD4i) antibodies, 17b, 48d, 412d, m6, m9 and X5, were prepared as previously described (Ryu et al., Nature 348:419, 1990; Kwong et al., J. Biol. Chem. 274:4115, 1999; Huang et al., Proc. Natl. Acad. Sci. USA 101:2706, 2004; Zhang et al., J. Mol. Biol. 335:209, 2004; Moulard et al., Proc. Natl. Acad. Sci. USA 99:6913, 2002). Preparations of gp120 complexes followed procedures that were essentially the same as previously described (Kwong et al., J. Biol. Chem. 274:4115, 1999). Briefly, glycans were removed by digestion with endoglycosidases H and D to leave only the protein proximal N-acetylglucosamine and 1,6 fucose residues. The 2-domain CD4 was added, the binary complexes passed through a concanavalin A column to remove any gp120 proteins with uncleaved N-linked glycan, and the complexes further purified by gel filtration (Hiload 26/60 Superdex S200 prep grad, Amersham). Fab or scFv of CD4-induced (CD4i) antibodies were added and the ternary complexes purified by Superdex S200 chromatography. Purified complexes in 0.35 M NaCl, 2.5 mM Tris pH 7.0, 0.02% NaN3 were concentrated to 5-8 mg/ml. The following complexes were made (specified by strain of core+V3 gp120:soluble CD4 domain fragment:CD4-induced antibody type and fragment):
JR-FL:d1d2:17b Fab
JR-FL:d1d2:48d Fab
JR-FL:d1d2:412d Fab
JR-FL:d1d2:X5 Fab
JR-FL:d1d2
YU2:d1d2:48d Fab
YU2:d1d2:X5 Fab
HXBc2:d1d2:17b Fab
HXBc2:d1d2:48d Fab
HXBc2:d1d2:412d Fab
HXBc2:d1d2:X5 Fab
HXBc2:d1d2:m6 scFv
HXBc2:d1d2:m9 scFv
2) Robotic Screening of Crystallization Conditions
The gp120 complexes were screened robotically using vapor-diffusion sitting droplets composed of 50 nl protein combined with 50 nl crystallization solution (Lesley et al., Proc. Natl. Acad. Sci. USA 99:11664, 2002). 576 different commercially available crystallization solutions were used in each screen. JRFL complexes were screened with Hampton Research Screen I/II, Emerald Wizard Screen I/II, Emerald Wizard Cryo Screen I/II, Hampton Crystal Screen Cryo, Hampton PEG/Ion Screen, Hampton Grid Screens (ammonium sulfate, PEG 6000, MPD, and PEG/LiCl), and Syrrx Polymer Screen. YU2 and HXBc2 complexes were screened in the same manner except that the Hampton Research Index screen was substituted for the Emerald Wizard Cryo Screens. Pictures of crystallization drops were taken at 0, 1, 3, 7, 14, and 21 days after set-up, and the images inspected visually for protein crystals.
3) Crystallization Optimization
Initial crystals observed from robotic screens were reproduced and optimized manually using vapor-diffusion hanging droplets. A total of eight different crystal forms were grown to sizes suitable for testing diffraction quality. While most of the crystals diffracted to at best only 6-10 Å, one crystal consisting of JR-FL:d1d2:X5 Fab diffracted to at least 5 Å and was chosen for further optimization. Larger single crystals were produced by macroseeding (Thaller et al., J. Mol. Biol. 147:465, 1981): 1.5 μl of 5 mg/ml JR-FL:d1d2:X5 Fab was mixed with an equal volume of 1.3 M ammonium sulfate and placed over a 0.5 ml reservoir of 1.3 M ammonium sulfate; after 30 minutes, a single crystal was transferred directly to the droplet. Macroseeded crystals grew to 0.1×0.1×0.2 mm in 5-7 days.
This example describes the methods used to determine the structure of a gp120 with an extended loop to atomic resolution.
Data Collection
Crystals were dehydrated (Heras et al., Structure 11: 139, 2003) over 3 M ammonium sulfate reservoirs for 2-3 days. Dehydrated crystals were cross-linked over 20 μl of 1.5% glutaraldehyde for 1.5 hr using the procedure of Lusty (Lusty, J. Appl. Cryst. 32:106, 1999), transferred to a cryoprotectant solution containing 2 M ammonium sulfate, 60% (w/v) xylitol, 10% (w/v) erythritol and 5% (v/v) ethylene glycol for 1-2 minutes, covered with paratone-N, loop mounted, and flash-cooled to 100 K° for data collection. X-ray data were collected at a wavelength of 1.00 Å, using the intense 3rd generation undulator beam-line (SER-CAT) at the Advanced Photon Source, and processed and reduced with HKL2000 (Otwinowski and Minor, Methods Enymol. 276:307, 1997). The crystals were found to belong to space group P622 and to contain one complex per asymmetric unit. The diffraction was anisotropic, with stronger diffraction along the 6-fold axis. The crystal structure of JR-FL:d1d2:X5 Fab was solved by molecular replacement with CNS (Brunger et al., Acta Crystallogr. D 54:905, 1998). For gp120:CD4, a binary search model was constructed from YU2 core gp120 complexed to d1d2 as extracted from the previously determined ternary complex with 17b (pdb accession number, 1RZK) (Kwong et al., Structure 8:1329, 2000), with gp120 N-terminus (residues 83-86) and V4 region (residues 399-406) deleted. For X5 Fab, the structure of free X5 was used (pdb accession number, 1RHH) (Darbha et al., Biochemistry 43:1410, 2004). Cross-rotation and translation search with 15-4 Å data yielded Patterson correlation coefficients of 22.3% and 31.1% for YU2core:d1d2 and X5 Fab, respectively. The combined solution gave a Patterson correlation coefficient of 51.7%. By using the programs, O (Jones et al., Acta Crystallogr. A 47:110, 1991) for model building and CNS (Brunger et al., Acta Crystallogr. D54:905, 1998) for refinement, side-chains of the initial models were corrected, and the models subjected to torsion angle simulated annealing with slow cooling. Iterative manual fittings were carried out in B-value sharpened maps (−75 Å2; 2Fo−Fc) to enhance visual recognition of protein sidechain definition. Refinement in CNS, however, used unsharpened data, with strong 3 geometric constraints to maintain idealized stereochemistry. Statistics summarizing the X-ray crystallographic data and refinement are shown in Table 6.
TABLE 6
X-ray crystallographic data and refinement statistics
Data collection
Space group P622
Molecules per ASU 1
Wavelength, Å 1.00
Unit cell dimensions a = b = 226.0 Å, c = 98.0 Å
Resolution, Å* 50-3.30 (3.71-3.55, 3.55-3.42, 3.42-3.30)
Completeness, %* 86.6 (91.4, 50.7, 20.9)
No. of total reflections 186,823
No. of unique reflections 19,372
Redundancy* 9.6 (5.1, 4.3, 3.1)
I/σ* 26.2 (2.3, 1.5, 1.3)
Rsym, %*, ‡ 8.2 (38.8, 47.3, 50.5)
Refinement statistics (|F| > 0 σ)
Resolution, Å 20.0-3.30
No. of reflections 19,364
Rcryst, %*, § 31.7
Rfree, %*, §, || 34.7
Rmsd bond length, Å 0.0043#
Rmsd bond angles, ° 0.978#
Luzzatti error, Å 0.64
Average B-value, Å2 125
Ramachandran plot
Most favored, % 83.3
Additionally allowed, % 15.8
Generously allowed, % 0.8
Disallowed, % 0.1
*Values in parentheses are for the last three highest resolution shells.
‡ Rsym = Σ|I − <I>|/Σ<I>, where I is the observed intensity, and <I> is the average intensity of multiple observations of symmetry related reflections.
§ R = Σhkl||Fobs| − |Fcalc||/Σhkl|Fobs|
|| Rfree is calculated from 10% of the reflections excluded from refinement.
#The geometry was tightly restrained, as this was observed to improve the Rfree.
Model Analysis
All superpositions were performed using 1sqkab in CCP4 (Collaborative Computational Project, Acta Crystallogr. D50:760, 1994). Molecular surface interactions were calculated using MS (Connolly, J. Mol. Graph. 11:139, 1993). Figures were prepared using PyMOL (DeLano Scientific, San Carlos, Calif., 2002) and GRASP (Nicholls et al, Proteins Struct. Funct. Genet. 11:281, 1991).
Glycan Modeling
Asn-(N-acetylglucosamine)2(mannose)3 N-linked sugar cores were modeled following procedures described previously for the HXBc2 core (Wyatt et al., Nature 393:705, 1998). Briefly, JR-FL core with V3 and the HXBc2 core with modeled glycan were superimposed. Conserved sites of Nlinked glycan were transferred, and other sites were built manually, including glycans at 301 and 386. The core was fixed and the Asn and attached glycan were subjected to molecular dynamics.
Sequence Analysis
Analyses were carried out with only sequences with complete V3, limited to one sequence per individual, extracted from the Los Alamos HIV sequence database (hiv.lanl.gov/content/hiv-db) for all M group sequences that had coreceptor usage specified as either CCR5 or CXCR4. The B clade subset of the M group had the most coreceptor usage information for a single clade, and so it was also analyzed separately. Alignments were made from constant to variable regions, with the β-turn (GPGR analog) of the tip forced into alignment. The Shannon entropy (Shannon, Bell System Tech. 27:379, 1948) was calculated for each site, treating gaps inserted to maintain alignment and distinct amino acids as characters, and statistical analysis of the variation at each site comparing R5 and X4 viruses was performed by using a Monte Carlo randomization of the two data sets (Korber et al., J. Virol. 68:7467, 1994), with a Bonferroni correction to contend with multiple tests. An entropy score is actually a simple measure of the information content of a data set: when considered in this context, as a measure of amino acid diversity in the column of an alignment, it has the virtue of capturing both the range and distribution of observed amino acids. Zero indicates absolute conservation, and a score of 4.4 indicates complete randomness.
This example describes the analysis of the structural details of a gp120 with an extended loop.
The third variable region (V3) of the HIV-I gp120 envelope glycoprotein is immunodominant and contains features essential for coreceptor binding. Disclosed herein is the structure of the V3 loop in the context of an HIV-I gp120 core complexed to the CD4 receptor and to the X5 antibody at 3.5 angstrom resolution. Binding of gp120 to cell-surface CD4 positions V3 so that its coreceptor-binding tip protrudes 30 angstroms from the core toward the target cell membrane. The extended nature and antibody accessibility of V3 explain its immunodominance. Snapshots of the gp120 entry mechanism have been visualized through crystal structures of unliganded and CD4-bound states (Chen et al., Nature 433:834, 2005; Kwong et al., Nature 393:648, 1998). Prior to this disclosure an essential component of the coreceptor binding site, the third variable region (V3), was been absent from structural characterizations of the gp120 core. The structure of V3 in the context of core gp120 bound to CD4, described herein, reveals the entire coreceptor binding site. The V3 appears to act as a molecular hook, not only for snaring coreceptor but also for modulating subunit associations within the viral spike. Its extended nature is compatible with the elicitation of an immunodominant antibody response and the generation of broadly neutralizing antibodies to V3 epitopes.
The extreme glycosylation and conformational flexibility of gp120 inhibit crystallization. Variational crystallization and various technologies adapted from structural genomics were used to obtain crystals suitable for x-ray structural analysis (Kwong et al., J. Biol. Chem. 274:4115, 1999; Stevens and Wilson, Science 293:519 (2001). The gp120 core with V3 from JR-FL The crystallized JR-FL was derived from a JR-FL variant with two point mutants, Asn301Gln and Thr388Ala. These mutations removed two Nlinked glycans, and the resultant virus was more sensitive to neutralization but was otherwise functional (Koch et al., Virology 313:387, 2003), when complexed to CD4 (two domain) and the antigen-binding fragment (Fab) of the X5 antibody (Koch et al., Virology 313:387, 2003), formed hexagonal crystals that diffracted to approximately 3.5 Å resolution with x-rays provided by an Advanced Photon Source undulator beam line (SER-CAT) (Table 5). The structure was solved by molecular replacement and is shown in
The overall assembly of CD4, X5, and core gp120 resembled the previously determined individual structures of CD4 (Ryu et al., Nature 34:419, 1990; Wang et al., Nature 348:411, 1990) and of free X5 (Darbha et al., Biochemistry 43:1410, 2004) as well as the complex of core gp120 bound to CD4 (Kwong et al., Nature 393:648, 1998; Kwong et al., Structure 8:1329, 2000). For core gp120, some differences were observed in the variable loops and also at the N terminus, regions where variations in gp120 have previously been observed (Chen et al., Nature 433:834, 2005; Kwong et al., Nature 393:648, 1998; Kwong et al., Structure 8:1329, 2000; Huang et al., Structure 13:755, 2005). Structural resemblance was maintained around the base of V3, indicating that the previous truncation (Chen et al., Nature 433:834, 2005; Kwong et al., Nature 393:648, 1998; Kwong et al., Structure 8:1329, 2000; Huang et al., Structure 13:755, 2005) did not distort this region of the core. In X5, a large structural difference was observed for the third complementarity determining loop of the X5 heavy chain (CDR H3). Comparison of the refined structures of free X5 (Darbha et al., Biochemistry 43:1410, 2004) and bound X5 showed Ca movements of up to 17 Å, one of the largest induced fits observed for an antibody (
By integrating the two-site gp120 binding site on the coreceptor with the two-site coreceptor binding site that it is observe in the structure of V3 gp120 with an extended V3 loop, that the N terminus of the coreceptor reaches up and binds to the core and V3 base while the V3 tip of gp120 reaches down to interact with the second extracellular loop of the coreceptor (
This example describes the “prime-boost” immunization scheme used to generate a heightened immune response in a subject.
Based on the biophysical characterization of gp120 stabilized in the CD4 bound conformation performed an immunization scheme was performed whereby HXBc2 strain wild-type or cysteine-stabilized core gp120 proteins were used to prime the immune response for subsequent immunization with soluble, stabilized trimeric YU2 strain gp140-foldon molecules (Yang et al. J Virol. 76(9):4634-42, 2002). B-cells primed by the stabilized cores were primed for epitopes displayed preferentially only on the stabilized HX core CD4 binding site, or to other stabilized surfaces, efficiently presented only by the cysteine-stabilized cores.
Boosting with the gp140 trimeric molecules “immuno-focuses” primed B cells on shared and conserved determinants between the two immunogens and altering strains would not boost B cells directed at HX- or YU2-specific epitopes. Thus, the only B-cells boosted selectively by the trimer would be those that could bind efficiently both the stabilized core as well as the trimer. Thus, stabilized cores can stimulate B cells that could induce the CD4-bound or the b12 conformation in the gp140 trimers.
Based upon this scheme, HIV gp120 core and trimer proteins were expressed by transient transfection of 293 cells with the relevant plasmid DNA. Soluble proteins were purified from culture supernatants by affinity chromatography and maintained in PBS, pH 7.4. Each rabbit was injected at two sites by the intramuscular route in the hind leg with 50 ug of protein emulsified at 1:1 ratio in GSK AS01B adjuvant in a total volume of 1 ml. The rabbits were inoculated four times with emulsified HX wild-type or stabilized core proteins followed by two injections with the emulsified YU2 gp140 trimeric proteins. Inoculations were performed at approximate four week intervals and the immune sera were collected ten days following each injection. The presence of high-titer anti-gp120 antibodies were confirmed by ELISA. The ability to neutralize viral particles derived from selected HIV strains was determined in a luciferase-based HIV entry assay. Virus was incubated with pre- or post-immune sera and the percent neutralization in the immune sera was calculated as the decrease in entry relative to virus incubated with pre-immune sera or an irrelevant BSA protein-emulsified control. The tabulated results of the immunogenicity-neutralization are shown in
This example describes the neutralization of various HIV isolates with CD4 induced triggering.
Construction of DNA and Recombinant Adenoviruses
Plasmid DNA and Ad5-based first-generation (ΔE1, ΔE3) recombinant adenoviruses expressing different V loop deletions of gp140(ΔCFI) were constructed. HIV envelope genes encoding gp145(ΔCFI) (BaL) (Genbank accession No. M68893), gp145(ΔCFI) (clade C) (Genbank accession No. AF286227), gp145(ΔCFI) (CN54) (Genbank accession No. AX149771), and gp145(ΔCFI) (clade A) (Genbank accession No. U08794) were synthesized using human-preferred codons. gp145 (ΔCFI)(B)(V3/C/1AB) and gp145 (ΔCFI)(B)(V3/A/1AB) were made by replacing Ba1 V3 loop with shortened clade C V3(1AB) and clade A V3(1AB) sequences respectively.
Vaccination
Guinea pigs were intramuscularly immunized with 500 μg (in 400 μl PBS) of the gp145 version of plasmid DNA at week 0, 2, and 6. At week 14, the guinea pigs were boosted with 1011 particles (in 400 μl PBS) of recombinant replication defective adenovirus (rAd) expressing the corresponding gp140 version of the protein. Serum was collected at week −2 and week 16, aliquotted, and frozen at −20° C.
Virus Neutralization Assay
Single round of infection HIV-1 Env pseudoviruses were prepared by cotransfecting 293T cells with an Env expression plasmid containing a full gp160 env gene and an env-deficient HIV-1 backbone vector (pSG3ΔEnv). Virus-containing culture supernatants were harvested 2 days after transfection, centrifuged and filtered through 0.45-micron filter, and stored at −80° C. Pseudovirus neutralization was measured as a function of Tat-induced luciferase reporter gene expression after a single round of infection in TZM-bl cells. TZM-bl cells express CD4, CXCR4 and CCR5 and contain and integrated reporter gene for firefly luciferase under the control of an HIV-1 LTR. The level of viral infection was quantified by measurement of relative luciferase units (RLU) that are directly proportion to the amount of virus inputs. Briefly, 40 ul of virus was incubated for 30 minutes at 37° C. with serial dilutions of test serum samples (10 ul) in duplicate wells of a 96-well flat bottom culture plate. The final serum dilution was defined at the point of incubation with virus supernatant. 10,000 TZM-bl cells were then added to each well in a total volume of 20 ul and plates were incubated overnight at 37° C. in a 5% CO2 incubator. One set of eight wells received mock antibody followed by virus and cells (controls wells for virus entry) and a set of eight wells received cells with mock virus (to control for luciferase background). Viral input was set at a multiplicity of infection (moi) of approximately 0.1, which generally results in 100,000 to 400,000 RLU. After over night incubation, 150ul of fresh medium was added to each well and incubated for 24 hours at 37° C. in a 5% CO2 incubator. To determine RLU, cell culture medium was aspirated from wells followed by addition of 50 ul of cell lysis buffer (Promega, Madison, Wis.). 30 ul of cell lysate was transferred to wells of a black Optiplate (PerkinElmer) for measurement of luminescence using a Perkin-Elmer Victor-light luminometer that injects 50 ul of luciferase substrate reagent to each well just prior to reading RLU. To test for sCD4 triggering, two-domain sCD4 was added to the virus just prior to the addition of sera.
This example describes the selection of immunogenic fragments of stabilized gp120.
A nucleic acid molecule encoding a stabilized p120 fragment is expressed in a host using standard techniques (see above; see Sambrook et al., Molecular Cloning; A Laboratory Manual, Cold Spring Harbor Press, Cold Spring Harbor, N.Y.: 1989). Preferable gp120 fragment is expressed such that the gp120 fragment can be isolated or purified in sufficient quantity. The stabilized gp120 fragment that are expressed are analyzed by various techniques known in the art, such as immunoblot, and ELISA, and for binding to CD4 and mAbs directed to the CD4 binding site, for example the b12 antibody.
To determine the antigenic potential of stabilized p120 fragments, subjects such as mice, rabbits or other suitable subjects are immunized with stabilized p120 fragments. Sera from such immunized subjects are tested for antibody activity for example by ELISA with the expressed polypeptide. They are also tested in a CD4 binding assay, for example by qualitative biacore, and the binding of neutralizing antibodies, for example by using the b12 antibody. Thus, antigenic fragments of stabilized forms are selected to archive broadly reactive neutralizing antibody responses.
This example describes the strategies to mask portions of a stabilized gp120 polypeptide from non-neutralizing antibodies.
The polypeptide “new 9c” as set forth as SEQ ID NO: 1 includes residues at the base of the V3 loop, and restores recognition of the core by the CD4-induced antibodies, such as 17b. Individual and combination glycan mutations were designed in the context of the stabilized gp120 polypeptides disclosed herein (for example, such as set forth in SEQ ID NO: 2 or encoded by SEQ ID NO: 4-18) to prevent the elicitation of non-neutralizing antibodies. Using site-directed mutagenesis, specific Asn and Ser/Thr residues are incorporated into the 8b core. The Asn-X-Ser/Thr residues mediate the attachment of glycans to the designated asparagine residues by mammalian cell glycosylating enzymes in the endoplasmic reticulum. This scheme is used to mask the immunogenic but non-neutralizing surfaces present in gp120.
Typically, wild-type gp120 cores elicit antibodies in rabbits that bind more efficiently to the core proteins than to full length gp120 glycoproteins. It is likely that the cores, via their truncated loops and N- and C-termini, elicit antibodies to surfaces that are not exposed in monomeric gp120.
As another aspect of an overall strategy to optimize the stabilized core priming of a trimer boost, glycans are designed at selected densities on the stabilized core to dampen or eliminate unwanted core-specific responses based upon the 8b core-b12 structure disclosed herein. The optimized and proteins are expressed, purified, analyzed and tested for immunogenicity by themselves or in sequential prime-boost with the YU2 gp140 trimers.
To mask the surface recognized by 17b and other CD4-induced antibodies the following mutations were designed:
To mask surfaces other than the CD4 binding site, which includes the b12 epitope region, the following N-glycan addition sites were designed:
Glycan
Location
Mutation 1
Mutation 2
1
246
Q246N
2
267
E267N
E269T
3
97
K97N
D99T
4
103
Q103N
H105S
5
92
N94T
6
114
Q114N
L116T
7
222
G222N
A224T
8
201
I201N
Q203T
9
206
P206N
V208T
10
423
I423N
N425T
11
434
M434N
A436S
12
442
Q442N
R444T
13
210
F210N
P212T
Density 2
Glycan
Location
Mutation 1
Mutation 2
1
246
Q246N
2
97
K97N
D99T
3
103
Q103N
H105S
4
201
I201N
Q203T
5
206
P206N
V208T
6
434
M434N
A436S
7
442
Q442N
R444T
8
210
F210N
P212T
9
114
Q114N
L116T
Density 3
Glycan
Location
Mutation 1
Mutation 2
1
206
P206N
V208T
2
442
Q442N
R444T
3
114
Q114N
L116T
4
246
Q246N
5
434
M434N
A436S
Mutation 1 and Mutation 2 correspond to the N glycosylation consensus sequence: NxT/S where x is anything except proline. T is better than S for glycosylation. Blanks indicate positions where no mutations are necessary. These glysolated peptides are used to induce a immune response in a subject.
In view of the many possible embodiments to which the principles of the disclosed invention may be applied, it should be recognized that the illustrated embodiments are only preferred examples of the invention and should not be taken as limiting the scope of the invention. Rather, the scope of the invention is defined by the following claims. We therefore claim as our invention all that comes within the scope and spirit of these claims.
Xu, Ling, Mascola, John, Zhou, Tongqing, Wyatt, Richard, Nabel, Gary, Kwong, Peter, Sodroski, Joseph, Dey, Barna, Yuan, Wen, Xiang, Shi-hua, Huang, Chih-Chin
| Patent | Priority | Assignee | Title |
| Patent | Priority | Assignee | Title |
| 5869624, | Mar 26 1993 | PROGENICS PHARMACEUTICALS, INC | HIV-1 vaccines, antibody compositions related thereto, and therapeutic and prophylactic uses thereof |
| 5922325, | Oct 26 1990 | Rutgers, The State University of New Jersey | Synergistic neutralization of HIV-1 by human monoclonal antibodies and other antibodies directed against the v3 loop and the CD-4 binding site of GP-120,and the use for immunotherapy of HIV-1 infection |
| 6432675, | Jun 18 1992 | R CREA & COMPANY | Combinatorial polypeptide antigens |
| 6710173, | Jun 25 1999 | AARON DIAMOND AIDS RESEARCH CENTRE ADARC | Stabilized viral envelope proteins and uses thereof |
| 6716429, | Oct 01 1997 | Dana-Farber Cancer Institute | Stabilization of envelope glycoprotein trimers by disulfide bonds introduced into a gp 41 glycoprotein ectodomain |
| 6908617, | Nov 10 1997 | The Trustees of Columbia University in the City of New York | Glycosylated modified primate lentivirus envelope polypeptides |
| 7022324, | Jun 25 1999 | Progenics Pharmaceuticals, Inc. | Stabilized viral envelope proteins and uses thereof |
| 7048929, | Nov 10 1997 | The Trustees of Columbia University in the City of New York | Stabilized primate lentivirus envelope glycoproteins |
| 20050025779, | |||
| WO58438, | |||
| WO172123, | |||
| WO2007030637, | |||
| WO9924465, | |||
| WO9924553, |
| Date | Maintenance Fee Events |
| Dec 05 2011 | ASPN: Payor Number Assigned. |
| Apr 27 2015 | M1551: Payment of Maintenance Fee, 4th Year, Large Entity. |
| Jun 17 2019 | REM: Maintenance Fee Reminder Mailed. |
| Dec 02 2019 | EXP: Patent Expired for Failure to Pay Maintenance Fees. |
| Date | Maintenance Schedule |
| Oct 25 2014 | 4 years fee payment window open |
| Apr 25 2015 | 6 months grace period start (w surcharge) |
| Oct 25 2015 | patent expiry (for year 4) |
| Oct 25 2017 | 2 years to revive unintentionally abandoned end. (for year 4) |
| Oct 25 2018 | 8 years fee payment window open |
| Apr 25 2019 | 6 months grace period start (w surcharge) |
| Oct 25 2019 | patent expiry (for year 8) |
| Oct 25 2021 | 2 years to revive unintentionally abandoned end. (for year 8) |
| Oct 25 2022 | 12 years fee payment window open |
| Apr 25 2023 | 6 months grace period start (w surcharge) |
| Oct 25 2023 | patent expiry (for year 12) |
| Oct 25 2025 | 2 years to revive unintentionally abandoned end. (for year 12) |